Biodegradable drug delivery compositions

ABSTRACT

A biodegradable drug delivery compositions comprising a triblock copolymer containing a polyester and a polyethylene glycol and a diblock copolymer containing a polyester and an end-capped polyethylene glycol, as well as a pharmaceutically active principle is disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of copending U.S. application Ser.No. 16/138,501 filed Sep. 21, 2018, which is a continuation of U.S.application Ser. No. 14/620,663 filed Feb. 12, 2015, now abandoned,which is a continuation of U.S. application Ser. No. 13/340,265, filedon Dec. 29, 2011, patented on May 5, 2015 as U.S. Pat. No. 9,023,897,which claims priority under 35 U.S.C. § 119(e) to U.S. ProvisionalApplication No. 61/428,007, filed on Dec. 29, 2010, all of which arehereby expressly incorporated by reference into the present application.

FIELD OF THE INVENTION

The present invention relates to biodegradable drug deliverycompositions comprising a triblock copolymer containing a polyester anda polyethylene glycol and a diblock copolymer containing a polyester andan end-capped polyethylene glycol, as well as a pharmaceutically activeprinciple. The ratio of triblock copolymer to diblock copolymer in thisformulation is 1:3 to 1:8 or 1:1 to 1:19 or 3:2 to 1:19. Methods forproducing these biodegradable drug compositions using organic solventsare also disclosed.

BACKGROUND OF THE PRESENT INVENTION

Drug delivery systems such as diblock and triblock copolymers have beenused to deliver a variety of drugs and are generally formulated todeliver specific drugs whether they are hydrophobic drugs or hydrophilicdrugs. Depending on the drug solubility these drug formulations differin polymer concentrations, types of polymers utilized, molecular weightsof the polymers and solvents used in the formulations.

Also the type of environment in which the drug is delivered is animportant consideration in formulating a drug delivery system. Thus,there exist drug delivery compositions that are prepared usingtemperature sensitive polymers, phase sensitive polymers, pH sensitivepolymers and photosensitive polymers. See, for example, K. AI-Tahami andJ. Singh “Smart Polymer Based Delivery Systems for Peptide andProteins,” Recent Patents on Drug Delivery & Formulation, 1: pages:65-71 Bentham Science Publishers, LTD. 2007.

U.S. Pat. No. 6,592,899 describes a PLA/PLGA oligomer combined with ablock copolymer for enhancing the solubility of a hydrophobic drug intoa hydrophilic environment. More specifically this polymer compositionhas a polyester oligomer having a molecular weight of between 400 and10,000 daltons and a biodegradable AB-type, ABA-type or BAB type blockcopolymer. The hydrophobic A part is a polyester, while the hydrophilicB part is a polyethylene glycol having a molecular weight of between2,400 and 4,999 daltons. This polymeric composition is soluble in anaqueous environment.

U.S. Pat. No. 6,541,033 describes a sustained release pharmaceuticalcomposition based on thermosensitive, biodegradable hydrogels,consisting of a block copolymer of PLA or PLGA and PEG, for thesustained delivery of biologically active agents, such as leptin. Thesustained release is for a period of a week or more and preferably up toone month.

Hydrogels containing triblock copolymers are described in U.S. Pat. No.6,350,812. These hydrogels retain water weight at least equal to thewater weight of the copolymer and are soft hydrogels.

None of the patents nor the literature cited above describes drugdelivery compositions that are injectable, in situ forming and arebiodegradable and turn into solid implants when injected into the body.The biodegradable drug compositions of the present invention comprisetriblock copolymers and diblock copolymers formulated in such a mannerthat the diblock copolymer serves as a reservoir while the triblockcopolymer acts as a frame in the formulations and increases the lifespanof the diblock copolymer.

Furthermore, the biodegradable drug delivery compositions of the presentinvention can be long acting formulations, which reduce the initialburst release of the drug and modulate the release rate of the drug overtime. This phenomenon is illustrated in the flattening of the drugrelease curves.

SUMMARY OF THE INVENTION

The present invention provides a biodegradable drug delivery compositioncomprising (a) a biodegradable triblock copolymer having the formula:

A_(v)-B_(w)-A_(x)

wherein A is a polyester and B is polyethylene glycol and v, w and x arethe number of repeat units ranging from 4 to 1090 and v=x or v≠x; (b) abiodegradable diblock copolymer having the formula:

C_(y)-A_(z)

wherein A is a polyester and C is an end-capped polyethylene glycol andy and z are the number of repeat units ranging from 3 to 237 or 7 to371, wherein the ratio of the biodegradable triblock copolymer of (a)and the biodegradable CA diblock copolymer of (b) is 1:1 to 1:19 or 3:2to 1:19 in said biodegradable drug composition; and (c) at least onepharmaceutically active principle.

The present invention provides a biodegradable drug delivery compositioncomprising (a) a biodegradable triblock copolymer having the formula:

A_(v)-B_(w)-A_(x)

wherein A is a polyester and B is polyethylene glycol and v, w and x arethe number of repeat units ranging from 6 to 1090 and v=x or v≠x; (b) abiodegradable diblock copolymer having the formula:

C_(y)-A_(z)

wherein A is a polyester and C is an end-capped polyethylene glycol andy and z are the number of repeat units ranging from 7 to 371, whereinthe ratio of the biodegradable triblock copolymer of (a) and thebiodegradable CA diblock copolymer of (b) is 1:3 to 1:8 in saidbiodegradable drug composition; and (c) at least one pharmaceuticallyactive principle.

The present invention provides a biodegradable drug delivery compositioncomprising (a) a biodegradable triblock copolymer having the formula:

A_(v)-B_(w)-A_(x)

wherein A is a polyester and B is polyethylene glycol and v, w and x arethe number of repeat units ranging from 4 to 1090, v and x being esterrepeat units and w being ethylene oxide repeat units and v=x or v≠x; (b)a biodegradable diblock copolymer having the formula:

C_(y)-A_(z)

wherein A is a polyester and C is an end-capped polyethylene glycol andy and z are the number of repeat units ranging from 3 to 237 or 7 to371, y being the number of ethylene oxide repeat units and z the numberof ester repeat units, wherein the ratio of the biodegradable triblockcopolymer of (a) and the biodegradable CA diblock copolymer of (b) is1:1 to 1:19 or 3:2 to 1:19 in said biodegradable drug composition; and(c) at least one pharmaceutically active principle.

The present invention provides a biodegradable drug delivery compositioncomprising (a) a biodegradable triblock copolymer having the formula:

A_(v)-B_(w)-A_(x)

wherein A is a polyester and B is polyethylene glycol and v, w and x arethe number of repeat units ranging from 6 to 1090, v and x being esterrepeat units and w being ethylene oxide repeat units and v=x or v≠x; (b)a biodegradable diblock copolymer having the formula:

C_(y)-A_(z)

wherein A is a polyester and C is an end-capped polyethylene glycol andy and z are the number of repeat units ranging from 7 to 371, y beingthe number of ethylene oxide repeat units and z the number of esterrepeat units, wherein the ratio of the biodegradable triblock copolymerof (a) and the biodegradable CA diblock copolymer of (b) is 1:3 to 1:8in said biodegradable drug composition; and (c) at least onepharmaceutically active principle.

A biodegradable drug delivery composition comprising: (a) abiodegradable triblock copolymer having the formula:

PLA_(v)-PEG_(w)-PLA_(x)

wherein v, w and x are the number of repeat units ranging from 4 to 1090and v=x or v≠x; (b) a biodegradable diblock copolymer having theformula:

PEG_(y)-PLA_(z)

wherein y and z are the number of repeat units ranging from 3 to 237 or3 to 371, wherein the ratio of the biodegradable triblock copolymer of(a) and the biodegradable diblock copolymer of (b) is 1:6 in saidbiodegradable drug composition and wherein the PEG in the diblock isend-capped; and (c) at least one pharmaceutically active principle.

A biodegradable drug delivery composition comprising: (a) abiodegradable triblock copolymer having the formula:

PLA_(v)-PEG_(w)-PLA_(x)

wherein v, w and x are the number of repeat units ranging from 6 to 1090and v=x or v≠x; (b) a biodegradable diblock copolymer having theformula:

PEG_(y)-PLA_(z)

wherein y and z are the number of repeat units ranging from 7 to 371,wherein the ratio of the biodegradable triblock copolymer of (a) and thebiodegradable diblock copolymer of (b) is 1:6 in said biodegradable drugcomposition and wherein the PEG in the diblock is end-capped; and (c) atleast one pharmaceutically active principle.

In yet another aspect a biodegradable drug delivery composition isprovided, which comprises: (a) a biodegradable triblock copolymerpresent in an amount of 2.0% to 45% (w %/w %) of the total compositionhaving the formula:

PLA_(v)-PEG_(w)-PLA_(x)

wherein v, w and x are the number of repeat units ranging from 4 to 1090or 6 to 1090 and v=x or v≠x; (b) a biodegradable diblock copolymerpresent in an amount of 8.0% to 50% (w %/w %) of the total compositionhaving the formula:

PEG_(y)-PLA_(z)

wherein y and z are the number of repeat units ranging from 3 to 237,wherein the ratio f the biodegradable triblock copolymer of (a) and thebiodegradable diblock copolymer of (b) is 1:4 or 3:2 to 1:19 or 1:1 to1:19 in said biodegradable drug composition and wherein the PEG in thediblock is end capped and (c) at least one pharmaceutically activeprinciple is present in an amount of 1% to 20% (w %/w %) of the totalcomposition or the at least one pharmaceutically active principle ispresent in an amount of 1 to 200 mg/ml.

In yet another aspect a biodegradable drug delivery composition isprovided, which comprises: (a) a biodegradable triblock copolymerpresent in an amount of 3.0% to 45% (w %/w %) of the total compositionhaving the formula:

PLA_(v)-PEG_(w)-PLA_(x)

wherein v, w and x are the number of repeat units ranging from 6 to 1090and v=x or v≠x; (b) a biodegradable diblock copolymer present in anamount of 8.0% to 50% (w %/w %) of the total composition having theformula:

PEG_(y)-PLA_(z)

wherein y and z are the number of repeat units ranging from 7 to 371,wherein the ratio of the biodegradable triblock copolymer of (a) and thebiodegradable diblock copolymer of (b) is 1:4 in said biodegradable drugcomposition and wherein the PEG in the diblock is end capped and (c) atleast one pharmaceutically active principle is present in an amount of1% to 20% (w %/w %) of the total composition or the at least onepharmaceutically active principle is present in an amount of 1 to 200mg/ml.

In another aspect a biodegradable drug delivery composition comprising:(a) a biodegradable triblock copolymer having the formula:

PLA_(v)-PEG_(w)-PLA_(x)

wherein v, w and x are the number of repeat units ranging from 4 to 1090and v=x or v≠x; (b) a biodegradable diblock copolymer having theformula:

mPEG_(y)-PLA_(z)

wherein y and z are the number of repeat units ranging from 3 to 237,wherein the ratio of the biodegradable triblock copolymer of (a) and thebiodegradable diblock copolymer of (b) is 1:1 to 1:19 or 3:2 to 1:19 insaid biodegradable drug composition; and (c) at least onepharmaceutically active principle.

In another aspect a biodegradable drug delivery composition comprising:(a) a biodegradable triblock copolymer having the formula:

PLA_(v)-PEG_(w)-PLA_(x)

wherein v, w and x are the number of repeat units ranging from 6 to 1090and v=x or v≠x; (b) a biodegradable diblock copolymer having theformula:

mPEG_(y)-PLA_(z)

wherein y and z are the number of repeat units ranging from 7 to 371,wherein the ratio of the biodegradable triblock copolymer of (a) and thebiodegradable diblock copolymer of (b) is 1:6 in said biodegradable drugcomposition; and (c) at least one pharmaceutically active principle.

In another aspect a biodegradable drug delivery composition comprising:(a) a biodegradable triblock copolymer having the formula:

PLA_(v)-PEG_(w)-PLA_(x)

wherein v, w and x are the number of repeat units ranging from 4 to 1090and v=x or v≠x; (b) a biodegradable diblock copolymer having theformula:

mPEG_(y)-PLA_(z)

wherein y and z are the number of repeat units ranging from 7 to 371 or3 to 237, wherein the ratio of the biodegradable triblock copolymer of(a) and the biodegradable diblock copolymer of (b) is 1:4 in saidbiodegradable drug composition; and (c) at least one pharmaceuticallyactive principle.

In another aspect a biodegradable drug delivery composition comprising:(a) a biodegradable triblock copolymer having the formula:

PLA_(v)-PEG_(w)-PLA_(x)

wherein v, w and x are the number of repeat units ranging from 6 to 1090and v=x or v≠x; (b) a biodegradable diblock copolymer having theformula:

mPEG_(y)-PLA_(z)

wherein y and z are the number of repeat units ranging from 7 to 371,wherein the ratio of the biodegradable triblock copolymer of (a) and thebiodegradable diblock copolymer of (b) is 1:4 in said biodegradable drugcomposition; and (c) at least one pharmaceutically active principle.

The biodegradable drug delivery compositions of the invention can have alactic acid to ethylene oxide molar ratio in the composition of between0.5 to 3.5 or 0.5 to 22.3 for the triblock copolymer and between 2 to 6or 0.8 to 13 for the diblock copolymer.

In another aspect the biodegradable drug delivery compositions of theinvention can have a lactic acid to ethylene oxide molar ratio in thecomposition of between 0.5 to 22.3 for the triblock copolymer andbetween 0.8 to 13 for the diblock copolymer.

In yet another aspect the biodegradable drug delivery compositions ofthe invention can have a lactic acid to ethylene oxide molar ratio inthe composition of between 0.5 to 2.5 for the triblock copolymer andbetween 3 to 5 for the diblock copolymer.

In one aspect the biodegradable drug delivery composition is aninjectable liquid that when it is inserted into the body of an animal orplant becomes a hardened implant.

In yet another aspect the biodegradable delivery drug composition can beused as a spatial formulation such that it can be applied onto or insidethe body of an animal or plant. For example, it can be dispensed duringsurgery to treat a wound or inside a plant to treat a virus.

In another aspect the biodegradable drug composition is prepared assmall solid particles, which are placed directly on the injured site ofthe body of an animal or plant.

In another aspect the biodegradable drug composition is in the form of arod implant.

A method for preparing the biodegradable drug delivery composition ofthe invention, said method comprising: (i) dissolving in an organicsolvent (a) a biodegradable ABA type block copolymer having the formula:

A_(v)-B_(w)-A_(x)

wherein A is a polyester and B is polyethylene glycol and v, w and x arethe number of repeat units ranging from 6 to 1090 wherein v=x or v≠x;and (b) a biodegradable diblock copolymer having the formula:

C_(y)-A_(z)

wherein A is a polyester and C is an end-capped polyethylene glycol andy and z are the number of repeat units ranging from 7 to 371 in a ratioof 1:3 to 1:8 (a):(b) to form a polymer mixture; and(ii) adding at least one pharmaceutically active principle to saidpolymer mixture, is yet another aspect of the invention.

A method for preparing the biodegradable drug delivery composition ofthe invention, said method comprising: (i) dissolving in an organicsolvent (a) a biodegradable ABA type block copolymer having the formula:

A_(v)-B_(w)-A_(x)

wherein A is a polyester and B is polyethylene glycol and v, w and x arethe number of repeat units ranging from 4 to 1090, v and x being esterrepeat units and w being ethylene oxide repeat units wherein v=x or v≠x;and (b) a biodegradable diblock copolymer having the formula:

C_(y)-A_(z)

wherein A is a polyester and C is an end-capped polyethylene glycol andy and z are the number of repeat units ranging from 3 to 237, y beingthe number of ethylene oxide repeat units and z the number of esterrepeat units in a ratio of 1:1 to 1:19 or 3:2 to 1:19 (a):(b) to form apolymer mixture; and(ii) adding at least one pharmaceutically active principle to saidpolymer mixture, is yet another aspect of the invention.

Yet another aspect the present invention provides a method for preparingthe biodegradable drug delivery composition of the present inventionsaid method comprising: (i) dissolving in an organic solvent (a) abiodegradable ABA type block copolymer having the formula:

A_(v)-B_(w)-A_(x)

wherein A is a polyester and B is polyethylene glycol and v, w and x arethe number of repeat units ranging from 6 to 1090 wherein v=x or v≠x;and (b) a biodegradable diblock copolymer having the formula:

C_(y)-A_(z)

wherein A is a polyester and C is an end-capped polyethylene glycol andy and z are the number of repeat units ranging from 7 to 371 in a ratioof 1:4 in (a):(b) to form a polymer mixture; (ii) adding at least onepharmaceutically active principle to said polymer mixture; and (iii)evaporating said solvent.

Yet another aspect the present invention provides a method for preparingthe biodegradable drug delivery composition of the present inventionsaid method comprising: (i) dissolving in an organic solvent (a) abiodegradable ABA type block copolymer having the formula:

A_(v)-B_(w)-A_(x)

wherein A is a polyester and B is polyethylene glycol and v, w and x arethe number of repeat units ranging from 4 to 1090 wherein v=x or v≠x;and (b) a biodegradable diblock copolymer having the formula:

C_(y)-A_(z)

wherein A is a polyester and C is an end-capped polyethylene glycol andy and z are the number of repeat units ranging from 3 to 237 in a ratioof 1:1 to 1:19 or 3:2 to 1:19 (a):(b) to form a polymer mixture; (ii)adding at least one pharmaceutically active principle to said polymermixture; and (iii) evaporating said solvent.

Yet another aspect the present invention provides a method for preparingthe biodegradable drug delivery composition of the present inventionsaid method comprising: (i) dissolving in an organic solvent (a) abiodegradable ABA type block copolymer having the formula:

A_(v)-B_(w)-A_(x)

wherein A is a polyester and B is polyethylene glycol and v, w and x arethe number of repeat units ranging from 6 to 1090, v and x being esterrepeat units and w being ethylene oxide repeat units wherein v=x or v≠x;and (b) a biodegradable diblock copolymer having the formula:

C_(y)-A_(z)

wherein A is a polyester and C is an end-capped polyethylene glycol andy and z are the number of repeat units ranging from 7 to 371, y beingthe number of ethylene oxide repeat units and z the number of esterrepeat units, in a ratio of 1:4 (a):b) to form a polymer mixture; (ii)adding at least one pharmaceutically active principle to said polymermixture; and (iii) evaporating said solvent.

Yet another aspect the present invention provides a method for preparingthe biodegradable drug delivery composition of the present inventionsaid method comprising: (i) dissolving in an organic solvent (a) abiodegradable ABA type block copolymer having the formula:

A_(v)-B_(w)-A_(x)

wherein A is a polyester and B is polyethylene glycol and v, w and x arethe number of repeat units ranging from 4 to 1090, v and x being esterrepeat units and w being ethylene oxide repeat units wherein v=x or v≠x;and (b) a biodegradable diblock copolymer having the formula:

C_(y)-A_(z)

wherein A is a polyester and C is an end-capped polyethylene glycol andy and z are the number of repeat units ranging from 3 to 237, y beingthe number of ethylene oxide repeat units and z the number of esterrepeat units, in a ratio of 1:4 (a):(b) to form a polymer mixture; (ii)adding at least one pharmaceutically active principle to said polymermixture; and (iii) evaporating said solvent.

In the above methods the organic solvent can be present in an amount of40% to 74% (w %/w %) of the total composition. Mixtures of solvents canalso be used.

Other aspects and embodiments are set forth below, or will readily arisefrom the following description of the preferred embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the in vitro release rate of the drug fromformulations based on 40% P6R1(TB):dP2R4(DB) in ratios of 1:0 (-∘-), 1:2(-Δ-), 1:4 (-●-), 1:6 (-▾-) and 1:9 (-*-) over time in days. This graphshows that formulations based on TB:DB are sustaining the release formore than 30 days.

FIG. 2 is a graph showing the in vitro cumulative percent release curvefrom candidate formulations of FIG. 1 over time (days). This graphillustrates that the initial burst is reduced and the drug release curveis flattened in the combination of triblock copolymer and diblockcopolymer compositions compared to the triblock copolymer compositionalone. It should be noted that the 1:9 curve is overlapping the 1:4curve.

FIG. 3 is a graph showing the injectability of formulations based on 40%P6R1 (TB); dP2R4(DB) in various ratios ranging from 1:0 triblockcopolymer to diblock copolymer to 0:1 triblock copolymer to diblockcopolymer. This graph illustrates that all formulations are injectableusing a classical injection device.

FIG. 4 is a graph showing the in vitro cumulative percentage releasecurve from candidate formulations over time (days) of variouscompositions of the invention. The compositions described as numbers177, 246, 224, 225 and 250 are described in Table 1.

FIG. 5 is a graph showing the in vitro release rate from candidateformulations in micrograms per hour per gram of formulation (μg/h/gr offormulation) The compositions described as numbers 177, 246, 224, 225and 250 are described in Table 1.

FIG. 6 is a graph showing the M53 plasma concentration in nanograms permilliliter (ng/ml) over time in days. Day zero is the day that thecomposition was administered subcutaneously. The compositions indicatedas numbers 177, 246, 224, 225 and 250 are described in Table 1.

FIG. 7 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P0.2R5 (4 units of ethylene oxide and 24 units of lactic acid)mixed with various diblock copolymers (see Table 2 for details).

FIG. 8 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P0.2R14 (4 units of ethylene oxide and 58 units of lacticacid) mixed with various diblock copolymers (see Table 2 for details).

FIG. 9 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P0.2R22 (4 units of ethylene oxide and 89 units of lacticacid) mixed with various diblock copolymers (see Table 2 for details).

FIG. 10 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P0.4R4 (9 units of ethylene oxide and 41 units of lactic acid)mixed with various diblock copolymers (see Table 2 for details).

FIG. 11 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P0.4R7 (9 units of ethylene oxide and 67 units of lactic acid)mixed with various diblock copolymers (see Table 2 for details).

FIG. 12 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P0.6R1 (13 units of ethylene oxide and 26 units of lacticacid) mixed with various diblock copolymers (see Table 2 for details).

FIG. 13 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P0.6R3 (13 units of ethylene oxide and 40 units of lacticacid) mixed with various diblock copolymers (see Table 2 for details).

FIG. 14 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P0.6R4 (13 units of ethylene oxide and 55 units of lacticacid) mixed with various diblock copolymers (see Table 2 for details).

FIG. 15 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P1R2 (22 units of ethylene oxide and 47 units of lactic acid)mixed with various diblock copolymers (see Table 2 for details).

FIG. 16 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P1R3 (22 units of ethylene oxide and 68 units of lactic acid)mixed with various diblock copolymers (see Table 2 for details).

FIG. 17 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P1R4 (22 units of ethylene oxide and 88 units of lactic acid)mixed with various diblock copolymers (see Table 2 for details).

FIG. 18 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P2R2 (45 units of ethylene oxide and 88 units of lactic acid)mixed with various diblock copolymers (see Table 2 for details).

FIG. 19 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P2R3 (45 units of ethylene oxide and 157 units of lactic acid)mixed with various diblock copolymers (see Table 2 for details).

FIG. 20 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P2R5 (45 units of ethylene oxide and 216 units of lactic acid)mixed with various diblock copolymers (see Table 2 for details).

FIG. 21 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P3R1 (68 units of ethylene oxide and 66 units of lactic acid)mixed with various diblock copolymers (see Table 2 for details).

FIG. 22 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P3R2 (68 units of ethylene oxide and 154 units of lactic acid)mixed with various diblock copolymers (see Table 2 for details).

FIG. 23 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P3R3 (68 units of ethylene oxide and 218 units of lactic acid)mixed with various diblock copolymers (see Table 2 for details).

FIG. 24 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P6R0.9 (136 units of ethylene oxide and 125 units of lacticacid) mixed with various diblock copolymers (see Table 2 for details).

FIG. 25 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P6R1.6 (136 units of ethylene oxide and 218 units of lacticacid) mixed with various diblock copolymers (see Table 2 for details).

FIG. 26 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P6R2 (136 units of ethylene oxide and 272 units of lacticacid) mixed with various diblock copolymers (see Table 2 for details).

FIG. 27 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P2R4 (45 units of ethylene oxide and 157 units of lactic acid)mixed with diblock copolymer dP.4R6 (7 units of ethylene oxide and 42units of lactic acid) at different ratios (see Table 2 for details).

FIG. 28 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P2R4 (45 units of ethylene oxide and 157 units of lactic acid)mixed with diblock copolymer dP.6R5 (12 units of ethylene oxide and 54units of lactic acid) at different ratios (see Table 2 for details).

FIG. 29 is a graph showing the in vitro cumulative percent release ofacetaminophen over time (days) from formulations based on triblockcopolymer P2R5 (45 units of ethylene oxide and 216 units of lactic acid)mixed with diblock copolymer dP0.2R13 (3 units of ethylene oxide and 39units of lactic acid) at different ratios (see Table 2 for details).

FIG. 30 is a graph showing the in vitro release rate of buprenorphineover time (days) from formulations n^(o)33 (10% BN/8% P2R2/32%dP0.4R10), n^(o)47 (10% BN/8% P2R2/32% dP1R3) and n^(o)58 (10% BN/10%P.4R8/40% dP1R2).

FIG. 31 is a graph showing the plasma concentration of buprenorphineover time (days) in rats injected with formulations n^(o)33 (10% BN/8%P2R2/32% dP0.4R10), n^(o)47 (10% BN/8% P2R2/32% dP1R3) and n^(o)58 (10%BN/10% P0.4R8/40% dP1R2).

FIG. 32 is a graph showing the in vitro release rate of risperidone overtime (days) from formulations based on triblock polymer P2R5 (45 unitsof ethylene oxide and 216 units of lactic acid) mixed with diblockpolymer dP0.2R13 (3 units of ethylene oxide and 39 units of lactic acid)at different ratios (see Table 2 for details).

FIG. 33 is a graph showing the plasma concentration of risperidone and9-OH risperidone over time (days) in rats injected with formulationsn^(o)10 (5% RSP/16% P2R2/24% dP2R2/DMSO), n^(o)29 (10% RSP/24% P1R4/16%dP0.4R5/DMSO) and n^(o)31 (10% RSP/18% P2R4/12% dP0.4R5/DMSO).

FIG. 34 is a graph showing the plasma concentration of ivermectin overtime (days) in dogs injected with formulations n^(o)7 (5% IVM/15%P3R3/25% dP0.4R5/DMSO), n^(o)9 (5% IVM/15% P2R4/25% dP2R3/DMSO) andn^(o)10 (5% IVM/15% P2R5/25% dP2R2/DMSO).

DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used herein the term “biodegradable” means that the triblock anddiblock copolymers will after a period of time erode or degrade in vivoto form smaller non-toxic components.

The term “parental administration” encompasses intramuscular,intraperitoneal, intra-abdominal, subcutaneous, intravenous andintraarterial. It also encompasses intradermal, intracavemous,intravitreal, intracerebral, intrathecal, epidurall and intraosseousadministration.

The term “animals” encompasses all members of the Kingdom Animalia.

As used herein the term “plant” encompasses all members of the PlantKingdom.

“Active principle” means a drug or medicine for treating various medicalillnesses. Thus active principles, drugs and medicines are usedinterchangeably. The term drug or active principle as used hereinincludes without limitation physiologically or pharmacologically activesubstances that act locally or systemically in the body of an animal orplant. At least one active principle is present in the biodegradabledrug composition of the invention.

As used herein “disease” means any disorder in a human, animal or plantcaused by infection, diet, or by faulty functioning of a process.

The term “implant” means that the drug delivery compositions areinjectable, are in situ forming and are biodegradable and turn intosolid implants when injected into the body. Thus, that the formulationsthat are synthesized are liquids such that they can be easily injectedthrough a syringe without excessive force.

The term “spatial formulations” encompass any formulations that can beapplied on or into the animal or plant body and do not necessarily haveto be administered through a syringe.

As used herein “repeat units” are the fundamental recurring units of apolymer.

By “end-capped polyethylene glycol” (cPEG) refers to PEG's in which oneterminal hydroxyl group is reacted and includes alkoxy-capped PEG's,urethane-capped PEG's ester-capped PEG's and like compounds. The cappinggroup is a chemical group which does not contain a chemical functionsusceptible to react with cyclic esters like lactide, glycolactide,caprolactone and the like or other esters and mixtures thereof. Thereaction of an end-capped PEG polymer with lactide generates a diblockcPEG-PLA copolymer.

As used herein polyethylene glycol, as abbreviated PEG throughout theapplication, is sometimes referred to as poly(ethylene oxide) orpoly(oxyethylene) and the terms are used interchangeably in the presentinvention.

The abbreviation of “PLA” refers to poly(lactic acid).

The abbreviation of “PLGA” refers to poly(lacticrco-glycolic acid).

The abbreviation “T” or “TB” refers to a triblock copolymer(s), whilethe abbreviation “D” or “DB” refers to a diblock copolymer(s).

The term “diblock” as used herein refers, for example, to an end-cappedPEG-polyester copolymer. “mPEG” refers to methoxy polyethylene glycol.

The term “triblock” refers, for example, to a polyester-PEG-polyestercopolymer.

The LA/EO ratio refers to the molar ratio of lactic acid units toethylene oxide units that is present in the biodegradable drug deliverycomposition. It is determined experimentally by NMR. The LA/EO molarratio of the combined triblock copolymer can range from 0.5 to 3.5. Inanother aspect the LA/EO molar ratio in the triblock can range from 0.5to 2.5 in the biodegradable drug delivery composition described herein.In yet another aspect the LA/EO ratio in the triblock can range from 0.5to 22.3.

The LA/EO ratio in the diblock can range from 2 to 6. In another aspectthe LA/EO ratio in the diblock can range from 3 to 5 in thebiodegradable drug delivery composition. In another aspect the LA/EOratio in the diblock can range from 0.8 to 13.

The degree of polymerization or DP is the number of repeat units in anaverage polymer chain at time t in a polymerization reaction. Forexample, the degree of polymerization for PEG is about 45 to 170 or itcan be 4 to 273 or 3 to 45, while for PLA it can range from about 84 to327 or it can be 24 to 682 or 7 to 327.

The present invention thus relates to a biodegradable drug compositioncomprising a triblock copolymer and a diblock copolymer. Thebiodegradable triblock copolymer has the formula: A_(v)-B_(w)-A_(x),wherein A is a polyester and B is polyethylene glycol and v, w and x arethe number of repeat units ranging, for example, from 4 to 1090 or from6 to 1090 and v=x or v≠x. w is the degree of polymerization (number ofrepeat units) for PEG. The degree of polymerization for DP-PEG iscalculated by dividing the PEG molecular weight by the EO unit molecularweight (44 Da). v+x equals the degree of polymerization (number ofrepeat units) for PLA. DP-PLA is calculated by multiplying DP-PEG by theLA/EO ratio.

However the number of repeat units of v, w and x in the triblockcomposition may vary due to the targeted time of release of the activeprinciple and the type of active principle itself. Therefore the numberof repeat units in the triblock of v, w and x can range from 8 to 1090,from 10 to 850, from 20 to 700, from 30 to 650 and v=x or v≠x. Forinstance, w can be 273, while x+y can be 682 and v=x or v≠x or w can be136 and x+y can be 273 and v=x or v≠x or w can be 45.5 and x+y can be546 or w can be 273 and x+y can be 136.

The size of the PEG in the triblock can range from 194 Da to 12,000 Da.

The polyester in the triblock can be polylactic acid (PLA),polycaprolactone (PCL), polyglycolic acid (PGA) or polyhydroxyalkanoate(PHA). In one embodiment the polyester that is used is polylactic acid.

The triblock copolymer is then combined with a biodegradable diblockcopolymer having the formula: C_(y)-A_(z). wherein A is a polyester andC is an end-capped polyethylene glycol and y and z are the number ofrepeat units ranging from 7 to 371 or from 3 to 327. This combinationhas a ratio of triblock copolymer to diblock copolymer ranging from 1:3to 1:8 or 1:1 to 1:19 or 3:2 to 1:19.

Examples of end-capped polyethylene glycols include alkoxy capped PEG'ssuch as methoxyPEG or ethoxyPEG, urethane-capped PEG's, ester-cappedPEG's, amine-capped PEG's and amide-capped PEG's. This list ofend-capped PEG's is not exhaustive and a person skilled in the art wouldrecognize additional end-capped PEG's, which are not listed.

However the number of repeat units (degree of polymerization (DP)) of yand z in the diblock composition may also vary. Thus, y can, forexample, range from 7 to 43 or 3 to 45 and z can range from 32 to 123 or7 to 327. For example, y can be 25 and z can be 123, y can be 34.5 and zcan be 123 or y can be 45 and z can be 32. The degree of polymerizationfor DP-PEG is calculated by dividing the PEG molecular weight of thecapped PEG by the EO unit molecular weight (44 Da). The DP-PLA iscalculated by multiplying DP-PEG by the LA/EO ratio,

The polyester in the diblock can be polylactic acid (PLA),polycaprolactone (PCL), polyglycolic acid (PGA), poly(lactic-co-glycolicacid) (PLGA) or polyhydroxyalkanoate (PHA). In one embodiment thepolyester that is used is polylactic acid. In another embodiment thepolyester is poly(lacti-co-glycolic acid).

In another aspect the present invention provides a biodegradable drugdelivery composition comprising (a) a biodegradable triblock copolymerhaving the formula:

A_(v)-B_(w)-A_(x)

wherein A is a polyester and B is polyethylene glycol and v, w and x thenumber of are repeat units ranging from 4 to 1090 or from 6 to 1090, vand x being ester repeat units and w being ethylene oxide repeat unitsand v=x or v≠x; (b) a biodegradable diblock copolymer having theformula:

C_(y)-A_(z)

wherein A is a polyester and C is an end-capped polyethylene glycol andy and z are the number of repeat units ranging from 7 to 371 or 3 to237, y being the number of ethylene oxide repeat units and z the numberof ester repeat units, wherein the ratio of the biodegradable triblockcopolymer of (a) and the biodegradable CA diblock copolymer of (b) is1:3 to 1:8 or 1:1 to 1:19 or 3:2 to 1:19 in said biodegradable drugcomposition; and (c) at least one pharmaceutically active principle.

In another aspect the present invention provides a biodegradable drugdelivery composition comprising a biodegradable triblock copolymerhaving the formula: PLA_(v)-PEG_(w)-PLA_(x), wherein v, w and x are thenumber of repeat units ranging from 4 to 1090 or 6 to 1090 and v=x orv≠x; a biodegradable diblock copolymer having the formula:mPEG_(y)-PLA_(z). wherein y and z are the number of repeat units rangingfrom 7 to 371 or 3 to 327, wherein the ratio of the biodegradabletriblock copolymer and the biodegradable diblock copolymer is 1:6 insaid biodegradable drug composition; and at least one pharmaceuticallyactive principle.

In another aspect a biodegradable drug delivery composition comprising:(a) a biodegradable triblock copolymer having the formula:

PLA_(v)-PEG_(w)-PLA_(x)

wherein v, w and x are the number of repeat units ranging from 4 to 1090or 6 to 1090 and v=x or v≠x; (b) a biodegradable diblock copolymerhaving the formula:

mPEG_(y)-PLA_(z)

wherein y and z are the number of repeat units ranging from 7 to 371 or3 to 237, wherein the ratio of the biodegradable triblock copolymer of(a) and the biodegradable diblock copolymer of (b) is 1:4 in saidbiodegradable drug composition; and (c) at least one pharmaceuticallyactive principle.

The ratio of the biodegradable triblock copolymer of (a) and thebiodegradable CA diblock copolymer of (b) is 1:3 to 1:8 or 1:1 to 1:19or 3:2 to 1:19 in said biodegradable drug composition. In one embodimentthe ratio of the biodegradable triblock copolymer of and thebiodegradable CA diblock copolymer is selected from the group of 1:3,1:4, 1:5, 1:6, 1:7 and 1:8 or 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8,1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18 and 1:19. Itcan also be 3:2. In another aspect the ratio of the triblock to thediblock is 1:6.

The length of the polyester chain is defined by its polyester toethylene oxide molar ratio, which is between 0.5 to 3.5 or 0.5 to 2.5 or0.5 to 22.3 for the triblock copolymer and 3 to 5 or 2 to 6 or 0.8 to 13for the diblock copolymer. Thus, for example, if polylactic acid is usedthe chain length is defined by the lactic acid/ethylene oxide molarratio. Similarly if polyglycolic acid is used, the chain length isdefined by the polyglycolic acid/ethylene oxide molar ratio or thepolycaprolactone/ethylene oxide molar ratio or theolyhydroxyalkanoate/ethylene oxide molar ratio. Ifpoly(lactic-co-glycolic) acid is used the chain length is defined by theratio of LA+G/EO.

The mass of the end-capped polyethylene glycol can range from 164 Da to2,000 Da or from 100 Da to 2 kDa. It can range in the lower 100 to 300Da range or in the 1 kDa to 2 kDa range.

The size of the polyethylene glycol chain ranges from 200 Da to 12 kDain the biodegradable drug delivery composition or it can range from 400Da to 12 kDa or 194 Da to 12 kDA.

The polymers are present in an amount of 20% to 50% (w %/w %) of thetotal weight of the composition. In another aspect the total weight ofthe polymers present in the biodegradable drug composition is 30% to 50%(w %/w %) of the total weight of the composition. In yet another aspectthe polymers are present in the biodegradable drug composition at 40% to50% (w %/w %) of the total weight of the composition.

Thus, the triblock copolymer is present in an amount of 3.0% to 45% (w%/w %) of the total weight of the composition. In another aspect thetriblock copolymer is present in an amount of 6% to 10% (w %/w %) of thetotal weight of the composition. In yet another aspect the triblockcopolymer is present in an amount of 20% to 40% (w %/w %) of the totalweight of the composition.

Likewise the diblock copolymer can be present in the biodegradable drugcomposition in an amount of 8% to 50% (w %/w %) of the total weight ofthe composition. In another aspect the diblock copolymer is present inan amount of 10% to 20% (w %/w %) of the total weight of thecomposition. In yet another aspect the diblock copolymer is present inan amount of 20% to 40% (w %/w %) of the total weight of thecomposition.

The at least one pharmaceutically active principle is entrapped in thetriblock:diblock biodegradable drug delivery composition. Representativedrugs and biologically active agents to be used in the inventioninclude, without limitation, peptide drugs, protein drugs, desensitizingagents, antigens, vaccines, vaccine antigens, anti-infectives,antibiotics, antimicrobials, antiallergenics, anti-diabetics, steroidalanti-inflammatory agents, decongestants, miotics, anticholinergics,sympathomimetics, sedatives, hypnotics, psychic energizers,tranquilizers, androgenic steroids, estrogens, progestational agents,humoral agents, prostaglandins, analgesics, corticosteroids,antispasmodics, antimalarials, antihistamines, cardioactive agents,non-steroidal anti-inflammatory agents, antiparkinsonian agents,antihypertensive agents, beta-adrenergic blocking agents, nutritionalagents, gonadotrophin releasing hormone agonists, insecticides,anti-helminthic agents and the benzophenanthridine alkaloids.

Thus combinations of drugs can also be used in the biodegradable drugdelivery composition of this invention. For instance, if one needs totreat Lupus erythematosis, non-steroidal anti-inflammatory agents andcorticosteroids can be administered together in the present invention.

Veterinary medicaments such as medicines for the treatment of worms orvaccines for animals are also part of the present invention.

Viral medicaments for plants such as those viruses from Potyviridae,Geminiviridae, the Tospovirus genus of Bunyaviridiae and Banana streakvirus are also encompassed by the present invention. Also medicamentsfor tobacco mosaic virus, turnip crinkle, barley yellow dwarf, ring spotwatermelon and cucumber mosaic virus can be used in the biodegradabledrug delivery composition of the invention.

To those skilled in the art, other drugs or biologically active agentsthat can be released in an aqueous environment can be utilized in thedescribed delivery system. Also, various forms of the drugs orbiologically active agents may be used. These include without limitationforms such as uncharged molecules, molecular complexes, salts, ethers,esters, amides, etc., which are biologically activated when injectedinto the animal or plant or used as a spatial formulation such that itcan be applied on or inside the body of an animal or plant or as a rodimplant.

The pharmaceutically effective amount of an active principle may varydepending on the active principle, the extent of the animal's or plantsmedical condition and the time required to deliver the active principle.There is no critical upper limit on the amount of active principleincorporated into the polymer solution except for that of an acceptablesolution or dispersion viscosity for injection through a syringe needleand that it can effectively treat the medical condition withoutsubjecting the animal or plant to an overdose. The lower limit of theactive principle incorporated into the delivery system is dependentsimply upon the activity of the active principle and the length of timeneeded for treatment.

For instance some active principles may be present in the biodegradabledrug delivery composition from 10 to 200 mg/ml. In another aspect thedrugs should be present in the amount of 10 to 40 μg/ml. For a smallmolecule, for instance, the active principle can be loaded as high as100 to 200 mg per ml.

Generally the pharmaceutically active principle is present in an amountof 1% to 20% (w %/w %) of the total weight of the composition. Inanother aspect the active principle is present in 1% to 4% (w %/w %) ofthe total weight of the composition. In another aspect the activeprinciple is present in 2% to 4% (w %/w %) of the total weight of thecomposition. In yet another aspect the active principle, which is asmall molecule, is present in an amount of 10% to 20% (w %/w %) of thetotal weight of the composition.

In the biodegradable drug delivery composition of the present invention,the pharmaceutically effective amount can be released gradually over anextended period of time. This slow release can be continuous ordiscontinuous, linear or non-linear and can vary due to the compositionof the triblock copolymer and diblock copolymer. Thus, the higher thelactic acid content of the triblock and diblock copolymers in comparisonwith the polyethylene glycol content, as well as the amount of triblockand diblock copolymers present in the biodegradable drug composition thelonger the release of the active principle or drug. In other words, thehigher the LA/EO molar ratio and the greater weight percentage of thetriblock and diblock copolymers, the longer it will take for the activeprinciple to be released from the drug composition.

The active principle can be released for a duration of between 7 days to1 year or longer depending upon the type of treatment needed and thebiodegradable drug delivery composition used. In one aspect thebiodegradable drug delivery composition can deliver the active principlefor at least 7 days. In another aspect the biodegradable drug deliverycomposition can deliver the active principle for at least 30 days. Inone aspect the biodegradable drug delivery composition can deliver theactive principle for at least 90 days. In yet another aspect thebiodegradable drug delivery composition can deliver an active principlefor 1 year or longer.

The biodegradable drug delivery composition can be an injectable liquidat room temperature and be injected through a syringe without excessiveforce. But these biodegradable drug delivery compositions are also insitu forming and biodegradable and turn into solid implants wheninjected into the animal or plant. Alternatively the biodegradable drugcomposition is produced as a solid, prepared as small particles and usedas a powder which is sprinkled on the injured site. In another aspectthe drug delivery composition is a rod implant, which can be implantedunder the skin or in another compartment in the body. In another aspectthe drug delivery composition can be prepared and applied as a film. Inyet another aspect the biodegradable delivery drug composition can beused as a spatial formulation such that it can be applied onto or insidethe body of an animal or plant. It can be applied anywhere on the body,including in the eye.

The biodegradable drug delivery composition can further comprise apharmaceutically acceptable carrier, adjuvant or vehicle. An acceptablecarrier can be saline, buffered saline and the like. It can be added tothe biodegradable drug delivery composition after its formulation withthe drug and diblock copolymer and triblock copolymer.

The adjuvant can be formulated simultaneously when mixing the drug. Inthis regard the adjuvants that can be used are alum, aluminum phosphate,calcium phosphate, MPL™, CpG motifs, modified toxins, saponins,endogenous stimulatory adjuvants such as cytokines, Freunds complete andincomplete adjuvants, ISCOM type adjuvants, muramyl peptides and thelike.

The vehicle can be any diluent, additional solvent, filler or binderthat may alter the delivery of the active principle when needed in thebiodegradable drug delivery composition. Examples include small amountsof triglycerides such as triacetin or tripropionin. The amount that canbe used in the present biodegradable drug deliver compositions of thepresent invention can vary from 12% to 20% (w %/w %). In one aspect atriacetin can be added in the formulation at 17.0% (w %/w %). In anotheraspect tripropionin (abbreviated herein as Tripro) can be added at 16%(w %/w %).

A method for preparing the biodegradable drug delivery composition ofthe invention is also encompassed by the invention. This methodcomprises: (i) dissolving in an organic solvent (a) a biodegradable ABAtype block copolymer having the formula: A_(v)-B_(w)-A_(x). wherein A isa polyester and B is polyethylene glycol and v, w and x are the numberof repeat units ranging from 4 to 1090 or 6 to 1090; and (b) abiodegradable diblock copolymer having the formula: C_(y)-A_(z), whereinA is a polyester and C is an end-capped polyethylene glycol and y and zare the number of repeat units ranging from 7 to 371 or 3 to 237 in aratio of 1:3 to 1:8 or 1:1 to 1:19 or 3.2 to 1:19 triblock to diblock toform a polymer mixture; and adding at least one pharmaceutically activeprinciple to said polymer mixture.

A method for preparing the biodegradable drug delivery composition ofthe invention, said method comprising: (i) dissolving in an organicsolvent (a) a biodegradable ABA type block copolymer having the formula:

A_(v)-B_(w)-A_(x)

wherein A is a polyester and B is polyethylene glycol and v, w and x arethe number of repeat units ranging from 4 to 1090 or 6 to 1090, v and xbeing ester repeat units and w being ethylene oxide repeat units whereinv=x or v≠x; and (b) a biodegradable diblock copolymer having theformula:

Cy-A_(z)

wherein A is a polyester and C is an end-capped polyethylene glycol andy and z are the number of repeat units ranging from 7 to 371 or 3 to237, y being the number of ethylene oxide repeat units and z the numberof ester repeat units, in a ratio of 1:3 to 1:8 or 1:1 to 1:19 or 3:2 to1:19 (a):(b) to form a polymer mixture; and(ii) adding at least one pharmaceutically active principle to saidpolymer mixture, is yet another aspect of the invention.

Yet another aspect the present invention provides a method for preparingthe biodegradable drug delivery composition of the present inventionsaid method comprising: (i) dissolving in an organic solvent (a) abiodegradable ABA type block copolymer having the formula:

A_(v)-B_(w)-A_(x)

wherein A is a polyester and B is polyethylene glycol and v, w and x arethe number of repeat units ranging from 4 to 1090 or 6 to 1090 whereinv=x or v≠x; and (b) a biodegradable diblock copolymer having theformula:

C_(y)-A_(z)

wherein A is a polyester and C is an end-capped polyethylene glycol andy and z are the number of repeat units ranging from 7 to 371 or 3 to 137in a ratio of 1:4 (a):b) to form a polymer mixture; (ii) adding at leastone pharmaceutically active principle to said polymer mixture; and (iii)evaporating said solvent.

Yet another aspect the present invention provides a method for preparingthe biodegradable drug delivery composition of the present inventionsaid method comprising: (i) dissolving in an organic solvent (a) abiodegradable ABA type block copolymer having the formula:

A_(v)-B_(w)-A_(x)

wherein A is a polyester and B is polyethylene glycol and v, w and x arethe number of repeat units ranging from 6 to 1090, v and x being esterrepeat units and w being ethylene oxide repeat units wherein v=x or v≠x;and (b) a biodegradable diblock copolymer having the formula:

C_(y)-A_(z)

wherein A is a polyester and C is an end-capped polyethylene glycol andy and z are the number of repeat units ranging from 7 to 371 or 3 to237, y being the number of ethylene oxide repeat units and z the numberof ester repeat units, in a ratio of 1:4 (a):b) to form a polymermixture; (ii) adding at least one pharmaceutically active principle tosaid polymer mixture; and (iii) evaporating said solvent.

Another embodiment provides a method for preparing the biodegradabledrug delivery composition of the invention, said method comprising: (i)dissolving in an organic solvent (a) a biodegradable ABA type blockcopolymer having the formula: A_(v)-B_(w)-A_(x), wherein A is apolyester and B is polyethylene glycol and v, w and x are the number ofrepeat units ranging from 4 to 1090 or 6 to 1090; and (b) abiodegradable diblock copolymer having the formula: C_(y)-A_(z). whereinA is a polyester and C is an end-capped polyethylene glycol and y and zare the number of repeat units ranging from 7 to 371 or 3 to 237 in aratio of 1:6 triblock to diblock to form a polymer mixture; adding atleast one pharmaceutically active principle to said polymer mixture; andevaporating said solvent. In this aspect no solvent is present in thebiodegradable drug delivery composition.

The organic solvent that can be used in the method described herein isselected from the group of: benzyl alcohol, benzyl benzoate, diethyleneglycol dimethyl ether (Diglyme), diethylene glycol monoethyl ether(DEGMEE), dimethyl isosorbide (DMI), dimethyl sulfoxide (DMSO), ethylacetate, ethyl benzoate, ethyl lactate, ethylene glycol monoethyl etheracetate, glycerol formal, methyl ethyl ketone, methyl isobutyl ketone,N-ethyl-2-pyrrolidone, N-methyl-2-pyrrolidinone (NMP), pyrrolidone-2,tetraglycol, triacetin, tributyrin, tripropionin (tripro), ortriethylene glycol dimethyl ether (triglyme) and mixtures thereof.

The organic solvent is present in an amount of 40% to 74% (w %/w %) ofthe total composition. In another aspect the organic solvent used in thepreparation of the biodegradable drug delivery composition is present inan amount of 50% to 60% (w %/w %) of the total composition. In yetanother aspect the solvent used in the preparation of the biodegradabledrug delivery composition is present in an amount of 60% to 70% (w %/w%) of the total composition.

Some mPEG-OH are contaminated with a small amount of OH-PEG-OH. Byfollowing the methods of the present invention and using thecontaminated mPEG-OH the final product would be mPEG-PLA contaminatedwith a small amount of PLA-PEG-PLA, which is encompassed by the presentinvention.

Another aspect of the present invention is the use of diblock andtriblock copolymers for the manufacture of a biodegradable drugcomposition. In this respect the biodegradable triblock copolymer hasthe formula: A_(v)-B-A_(x), wherein A is a polyester and B ispolyethylene glycol and v, w and x are the number of repeat unitsranging from 4 to 1090 or 6 to 1090 and v=x or v≠x. The polyester can bepolylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA)or polyhydroxyalkanoate (PHA). In one embodiment the polyester that isused is poly(lactic) acid.

The triblock copolymer is then combined with a biodegradable diblockcopolymer having the formula: C_(y)-A_(z), wherein A is a polyester andC is an end-capped polyethylene glycol and y and z are the number ofrepeat units ranging from 7 to 371 or 3 to 237. The polyester can bepolylactic acid (PLA), polycaprolactone (PCL), polyethylene adipate(PEA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid (PLGA) orpolyhydroxyalkanoate (PHA). In one embodiment the polyester that is usedis poly(lactic) acid.

The ratio of the biodegradable triblock copolymer of (a) and thebiodegradable CA diblock copolymer of (b) is 1:3 to 1:8 in saidbiodegradable drug composition. In one embodiment the ratio of thebiodegradable triblock copolymer of and the biodegradable CA diblockcopolymer is selected from the group of 1:3, 1:4, 1;5, 1:6, 1:7 and 1:8.or 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13,1:14, 1:15, 1:16, 1:17, 1:18 and 1:19. In another aspect the ratio ofthe triblock to the diblock is 1:6. It can also be 3:2.

The length of the polyester chain is defined by its polyester toethylene oxide molar ratio, which is between 0.5 to 3.5 or 0.5 to 2.5 or0.5 to 22.3 for the triblock and 3 to 5 or 2 to 6 or 0.8 to 13 for thediblock.

The mass of the end-capped polyethylene glycol can range from 100 Da to2 kDa or 164 Da to 2 kDa. It can range in the 100 to 300 Da range or inthe 1 kDa to 2 kDa range.

The size of the polyethylene glycol chain ranges from 200 Da to 12 kDain the biodegradable drug delivery composition or it can range from 400Da to 12 kDa or 194 Da to 12 kDa.

A number of embodiments and/or aspects of the invention have beendescribed. Nevertheless it will be understood that various modificationsmay be made without departing from the spirit and scope of theinvention.

EXAMPLES Example 1—Polymer Synthesis

Copolymers were synthesized according to the method described in theU.S. Pat. No. 6,350,812, incorporated herein by reference, with minormodifications. Typically, the necessary amount of PEG (gives thetriblock coploymer) or methoxy-PEG (gives the diblock copolymer) washeated at 65° C. and dried under vacuum for 2 hours in a reactor vessel.DL-lactide (corresponding to the targeted LA/EO molar ratio) and zinclactate ( 1/1000 of amount of lactide) were added. The reaction mixturewas first dehydrated by three short vacuum/N2 cycles. The reactionmixture was heated at 140° C. and rapidly degassed under vacuum. Thereaction was conducted for four days at 140° C. under constant nitrogenflow (0.2 bar). The reaction was cooled to room temperature and itscontent was dissolved in acetone and then subjected to precipitationwith ethanol. The product obtained was subsequently dried under reducedpressure. The final product was characterized by ¹H NMR for its lactatecontent. The triblock PLA-PEG-PLA polymers described herein were labeledPxRy where x represent the size of the PEG chain in kDa and y is theLA/EO molar ratio. The diblock mPEG-PLA polymers described herein werelabeled dPxRy where x represent the size of the PEG chain in kDa and yis the LA/E molar ratio.

Example 2—Formulation Preparation Specific for the Peptide M53

The formulations described herein were based on organic solution ofpolymers containing as the drug, the peptide M53, a GLP-1 analogue.Typically, 0.4 grams of polymers, corresponding to a mix of a diblockcopolymer and a triblock copolymer in defined mass ratio, were dissolvedin 0.57 grams of a biocompatible solvent at room temperature overnightunder constant magnetic stirring. The solvent was either a singlesolvent or a combination of solvents. The next day, 20 mg of drug wasadded to the polymer solution and stirred until complete dissolution.When the drug was not soluble in the solvent, a suspension of the drugin a polymer solution was obtained. Alternatively, the drug wasdissolved or suspended in the biocompatible solvent and the polymer(s)added subsequently. The formulations were loaded in a syringe beforeuse.

Example 3—the Formulations that were Prepared

Following Examples 1 and 2 various formulations were prepared, which areset forth in Table 1 for the peptide M63

TABLE 1 Triblock copolymer (TB) Diblock copolymer (DB) M53 PEG RatioRatio % % size (LA/ DP- DP- % No DB/TB (w/w) (w/w) Code (kDa) EO) PEGPLA (w/w) Code 10 4.0 4.0 10.0% P12R0.5 12 0.5 273 136 40.0% dP2R3 124.0 4.0 10.0% P12R3 12 2.5 273 682 40.0% dP2R3 21 4.0 4.0 10.0% P12R0.512 0.5 273 136 40.0% dP2R3 23 4.0 4.0 10.0% P12R3 12 2.5 273 682 40.0%dP2R3 34 4.0 4.0 10.0% P12R0.5 12 0.5 273 136 40.0% dP2R3 45 4.0 4.010.0% P12R3 12 2.5 273 682 40.0% dP2R3 66 4.0 4.0 10.0% P12R0.5 12 0.5273 136 40.0% dP2R3 68 4.0 4.0 10.0% P12R3 12 2.5 273 682 40.0% dP2R3 764.0 4.0 10.0% P12R0.5 12 0.5 273 136 40.0% dP2R3 78 4.0 4.0 10.0% P12R312 2.5 273 682 40.0% dP2R3 80 4.0 4.0 10.0% P12R0.5 12 0.5 273 136 40.0%dP2R3 82 4.0 4.0 10.0% P12R3 12 2.5 273 682 40.0% dP2R3 105 4.0 4.0 8.0% P6R0.9 3 0.9 136 123 32.0% dP2R4 116 4.0 4.0  8.0% P6R0.9 6 0.9136 123 32.0% dP2R4 123 4.0 4.0  8.0% P3R1 3 1.0 68 68 32.0% dP2R4 1244.0 4.0  8.0% P6R0.9 6 0.9 136 123 32.0% dP2R4 153 4.0 4.0  7.0% P12R0.512 0.5 273 136 28.0% dP2R4 159 4.0 4.0  7.0% P12R0.5 12 0.5 273 13628.0% dP2R4 169 5.7 2.0  6.0% PSR0.9 6 0.9 136 123 34.0% dP2R4 177 5.72.0  7.5% P6R0.9 6 0.9 136 123 42.5% dP2R4 198 9.0 4.0  4.0% P6R0.9 60.9 136 123 36.0% dP2R4 200 9.0 2.0  5.0% P6R0.9 3 0.9 136 123 45.0%dP2R3 203 4.0 2.0 10.0% P6R0.9 6 0.9 136 123 40.0% dP2R7 207 5.7 4.0 6.0% P6R0.9 6 0.9 136 123 34.0% dP2R4 209 4.0 2.0  9.0% P6R0.9 6 0.9136 123 36.0% dP2R7 210 4.0 2.0  8.0% P6R0.9 6 0.9 136 123 32.0% dP2R7221 9.0 4.0  5.0% PSR0.9 6 0.9 136 123 45.0% dP2R4 224 5.7 2.0  6.0%P6R0.9 6 0.9 136 123 34.0% dP2R4 225 9.0 2.0  5.0% P6R0.9 6 0.9 136 12345.0% dP2R4 230 5.7 2.0  7.5% P6R0.9 6 0.9 136 123 42.5% dP1R5 234 5.72.0  6.0% P6R0.9 6 0.9 136 123 34.0% dP1R5 241 5.9 2.0  6.5% P6R0.9 60.9 136 123 38.5% dP1R5 245 5.9 2.0  6.5% P2R2 2 2 45 91 38.5% dP1R5 2465.7 2.0  7.5% P2R2 2 2 45 91 42.5% dP1R5 247 9.0 2.0  5.0% P2R2 2 2 4591 45.0% dP1R5 250 9.0 4.0  5.0% P6R0.9 6 0.9 136 123 45.0% dP2R4Diblock copolymer (DB) Solvent Solvent PEG Ratio 1 2 size (LA/ DP- DP- %% No (kDa) EO) PEG PLA Name (w/w) Name (w/w) 10 2 3.2 45 143 DEGMEE46.0% 12 2 3.2 45 143 DEGMEE 46.0% 21 2 3.2 45 143 Diglyme 46.0% 23 23.2 45 143 Diglyme 46.0% 34 2 3.2 45 143 DMI 46.0% 45 2 3.2 45 143 DMI46.0% 66 2 3.2 45 143 Diglyme 46.0% 68 2 3.2 45 143 Diglyme 46.0% 76 23.2 45 143 DMSO 46.0% 78 2 3.2 45 143 DMSO 46.0% 80 2 3.2 45 143 Et46.0% Lactate 82 2 3.2 45 143 Et 46.0% Lactate 105 2 4.4 45 200 Diglyme56.0% 116 2 4.4 45 200 Diglyme 56.0% 123 2 4.3 45 195 DMSO 56.0% 124 24.3 45 195 DMSO 56.0% 153 2 4.3 45 195 DMSO 61.0% 159 2 4.3 45 195 DMSO44.0% Tracetin 17.0% 169 2 4.3 45 195 DMSO 58.0% 177 2 4.3 45 195 DMSO48.0% 198 2 4.3 45 195 Diglyme 37.0% Tripro 19.0% 200 2 3 45 136 DMSO48.0% 203 2 7.2 45 327 DMSO 48.0% 207 2 4.3 45 195 Diglyme 40.0% Tripro16.0% 209 2 7.2 45 327 DMSO 53.0% 210 2 7.2 45 327 DMSO 58.0% 221 2 4.345 195 Diglyme 33.0% Tripro 13.0% 224 2 4.3 45 195 Diglyme 41.4% Tripro16.6% 225 2 4.3 45 195 Diglyme 34.0% Tripro 13.6% 230 1 5.4 23 123 DMSO48.0% 234 1 5.4 23 123 Diglyme 41.4% Tripro 16.6% 241 1 5.4 23 123 DMSO53.0% 245 1 5.4 23 123 DMSO   53% 246 1 5.4 23 123 DMSO 48.0% 247 1 5.423 123 DMSO 48.0% 250 2 4.3 45 195 Diglyme 33.2% Tripro 12.8%

Example 4—Acetaminophen's Formulations Preparation

The formulations described herein were based on organic solution ofpolymers prepared as in Example 1, containing as the drug,acetaminophen. Typically, 0.4 grams of polymers, corresponding to a mixof a diblock copolymer and a triblock copolymer in defined mass ratio,were dissolved in 0.55 grams of dimethyl sulfoxide at room temperatureovernight under constant magnetic stirring. The next day, 50 mg ofacetaminophen was added to the polymer solution and stirred untilcomplete dissolution. The formulations were loaded in a syringe beforeuse. The composition of the various formulations is shown in Table 2below, where the solvent used is DMSO.

FIGS. 7 to 26 illustrate the results of these formulations which showall possible combinations of 15 triblock copolymers with 20 diblockscopolymers.

TABLE 2 Triblock copolymer (TB) Diblock copolymer (DB) Ratio RatioSolvent Exp Ratio % PEG (LA/ DP- DP- % PEG (LA/ DP- DP- % no DB/TB (w/w)Code (kDa) EO) PEG PLA (w/w) Code (kDa) EO) PEG PLA Name (w/w) 1 4.0  8%P0.2R14 0.2 14.5 4 58 32% dP0.2R6 0.2 5.8 3 17 DMSO 55% 2 4.0  8%P0.2R14 0.2 14.5 4 58 32% dP0.4R6 0.4 5.8 7 42 DMSO 55% 3 4.0  8%P0.2R14 0.2 14.5 4 58 32% dP0.6R5 0.6 4.6 12 54 DMSO 55% 4 4.0  8%P0.2R14 0.2 14.5 4 58 32% dP1R4 1.0 4.0 22 89 DMSO 55% 5 4.0  8% P0.2R140.2 14.5 4 58 32% dP2R3 2.0 2.8 45 125 DMSO 55% 6 4.0  8% P0.6R3 0.6 3.013 40 32% dP0.2R6 0.2 5.8 3 17 DMSO 55% 7 4.0  8% P0.6R3 0.6 3.0 13 4032% dP0.4R6 0.4 5.8 7 42 DMSO 55% 8 4.0  8% P0.6R3 0.6 3.0 13 40 32%dP0.6R5 0.6 4.6 12 54 DMSO 55% 9 4.0  8% P0.6R3 0.6 3.0 13 40 32% dP1R41.0 4.0 22 89 DMSO 55% 10 4.0  8% P0.6R3 0.6 3.0 13 40 32% dP2R3 2.0 2.845 125 DMSO 55% 11 4.0  8% P1R3 1.0 3.1 22 68 32% dP0.2R6 0.2 5.8 3 17DMSO 55% 12 4.0  8% P1R3 1.0 3.1 22 68 32% dP0.4R6 0.4 5.8 7 42 DMSO 55%13 4.0  8% P1R3 1.0 3.1 22 68 32% dP0.6R5 0.6 4.6 12 54 DMSO 55% 14 4.0 8% P1R3 1.0 3.1 22 68 32% dP1R4 1.0 4.0 22 89 DMSO 55% 15 4.0  8% P1R31.0 3.1 22 68 32% dP2R3 2.0 2.8 45 125 DMSO 55% 16 4.0  8% P2R3 2.0 3.545 157 32% dP0.2R6 0.2 5.8 3 17 DMSO 55% 17 4.0  8% P2R3 2.0 3.5 45 15732% dP0.4R6 0.4 5.8 7 42 DMSO 55% 18 4.0  8% P2R3 2.0 3.5 45 157 32%dP0.6R5 0.6 4.6 12 54 DMSO 55% 19 4.0  8% P2R3 2.0 3.5 45 157 32% dP1R41.0 4.0 22 89 DMSO 55% 20 4.0  8% P2R3 2.0 3.5 45 157 32% dP2R3 2.0 2.845 125 DMSO 55% 21 4.0  8% P3R2 3.0 2.3 68 154 32% dP0.2R6 0.2 5.8 3 17DMSO 55% 22 4.0  8% P3R2 3.0 2.3 68 154 32% dP0.4R6 0.4 5.8 7 42 DMSO55% 23 4.0  8% P3R2 3.0 2.3 68 154 32% dP0.6R5 0.6 4.6 12 54 DMSO 55% 244.0  8% P3R2 3.0 2.3 68 154 32% dP1R4 1.0 4.0 22 89 DMSO 55% 25 4.0  8%P3R2 3.0 2.3 68 154 32% dP2R3 2.0 2.8 45 125 DMSO 55% 26 4.0  8% P6R26.0 1.6 136 218 32% dP0.2R6 0.2 5.8 3 17 DMSO 55% 27 4.0  8% P6R2 6.01.6 136 218 32% dP0.4R6 0.4 5.8 7 42 DMSO 55% 28 4.0  8% P6R2 6.0 1.6136 218 32% dP0.6R5 0.6 4.6 12 54 DMSO 55% 29 4.0  8% P6R2 6.0 1.6 136218 32% dP1R4 1.0 4.0 22 89 DMSO 55% 30 4.0  8% PSR2 6.0 1.6 136 218 32%dP2R3 2.0 2.8 45 125 DMSO 55% 31 4.0  8% P0.2R6 0.2 5.9 4 24 32% dP0.2R20.2 2.2 3 7 DMSO 55% 32 4.0  8% P0.2R6 0.2 5.9 4 24 32% dP0.2R13 0.213.0 3 39 DMSO 55% 33 4.0  8% P0.2R6 0.2 5.9 4 24 32% dP0.4R2 0.4 2.0 714 DMSO 55% 34 4.0  8% P0.2R6 0.2 5.9 4 24 32% dP0.4R8 0.4 8.4 7 61 DMSO55% 35 4.0  8% P0.2R6 0.2 5.9 4 24 32% dP0.6R3 0.6 3.0 12 35 DMSO 55% 364.0  8% P0.2R6 0.2 5.9 4 24 32% dP0.6R5 0.6 5.1 12 60 DMSO 55% 37 4.0 8% P0.2R6 0.2 5.9 4 24 32% dP1R3 1.0 3.0 22 66 DMSO 55% 38 4.0  8%P0.2R6 0.2 5.9 4 24 32% dP1R5 1.0 5.4 22 119 DMSO 55% 39 4.0  8% P0.2R60.2 5.9 4 24 32% dP2R1 2.0 1.3 45 58 DMSO 55% 40 4.0  8% P0.2R6 0.2 5.94 24 32% dP2R5 2.0 5.3 45 237 DMSO 55% 41 4.0  8% P0.2R22 0.2 22.3 4 8932% dP0.2R2 0.2 2.2 3 7 DMSO 55% 42 4.0  8% P0.2R22 0.2 22.3 4 89 32%dP0.2R13 0.2 13.0 3 39 DMSO 55% 43 4.0  8% P0.2R22 0.2 22.3 4 89 32%dP0.4R2 0.4 2.0 7 14 DMSO 55% 44 4.0  8% P0.2R22 0.2 22.3 4 89 32%dP0.4R8 0.4 8.4 7 61 DMSO 55% 45 4.0  8% P0.2R22 0.2 22.3 4 89 32%dP0.6R3 0.6 3.0 12 35 DMSO 55% 46 4.0  8% P0.2R22 0.2 22.3 4 89 32%dP0.6R5 0.6 5.1 12 60 DMSO 55% 47 4.0  8% P0.2R22 0.2 22.3 4 89 32%dP1R3 1.0 3.0 22 66 DMSO 55% 48 4.0  8% P0.2R22 0.2 22.3 4 89 32% dP1R51.0 5.4 22 119 DMSO 55% 49 4.0  8% P0.2R22 0.2 22.3 4 89 32% dP2R1 2.01.3 45 58 DMSO 55% 50 4.0  8% P0.2R22 0.2 22.3 4 89 32% dP2R5 2.0 5.3 45237 DMSO 55% 51 4.0  8% P0.4R5 0.4 4.7 9 41 32% dP0.2R2 0.2 2.2 3 7 DMSO55% 52 4.0  8% P0.4R5 0.4 4.7 9 41 32% dP0.2R13 0.2 13.0 3 39 DMSO 55%53 4.0  8% P0.4R5 0.4 4.7 9 41 32% dP0.4R2 0.4 2.0 7 14 DMSO 55% 54 4.0 8% P0.4R5 0.4 4.7 9 41 32% dP0.4R8 0.4 8.4 7 61 DMSO 55% 55 4.0  8%P0.4R5 0.4 4.7 9 41 32% dP0.6R3 0.6 3.0 12 35 DMSO 55% 56 4.0  8% P0.4R50.4 4.7 9 41 32% dP0.6R5 0.6 5.1 12 60 DMSO 55% 57 4.0  8% P0.4R5 0.44.7 9 41 32% dP1R3 1.0 3.0 22 66 DMSO 55% 58 4.0  8% P0.4R5 0.4 4.7 9 4132% dP1R5 1.0 5.4 22 119 DMSO 55% 59 4.0  8% P0.4R5 0.4 4.7 9 41 32%dP2R1 2.0 1.3 45 58 DMSO 55% 60 4.0  8% P0.4R5 0.4 4.7 9 41 32% dP2R52.0 5.3 45 237 DMSO 55% 61 4.0  8% P0.4R8 0.4 7.7 9 67 32% dP0.2R2 0.22.2 3 7 DMSO 55% 62 4.0  8% P0.4R8 0.4 7.7 9 67 32% dP0.2R13 0.2 13.0 339 DMSO 55% 63 4.0  8% P0.4R8 0.4 7.7 9 67 32% dP0.4R2 0.4 2.0 7 14 DMSO55% 64 4.0  8% P0.4R8 0.4 7.7 9 67 32% dP0.4R8 0.4 8.4 7 61 DMSO 55% 654.0  8% P0.4R8 0.4 7.7 9 67 32% dP0.6R3 0.6 3.0 12 35 DMSO 55% 66 4.0 8% P0.4R8 0.4 7.7 9 67 32% dP0.6R5 0.6 5.1 12 60 DMSO 55% 67 4.0  8%P0.4R8 0.4 7.7 9 67 32% dP1R3 1.0 3.0 22 66 DMSO 55% 68 4.0  8% P0.4R80.4 7.7 9 67 32% dP1R5 1.0 5.4 22 119 DMSO 55% 69 4.0  8% P0.4R8 0.4 7.79 67 32% dP2R1 2.0 1.3 45 58 DMSO 55% 70 4.0  8% P0.4R8 0.4 7.7 9 67 32%dP2R5 2.0 5.3 45 237 DMSO 55% 71 4.0  8% P0.6R2 0.6 1.9 13 26 32%dP0.2R2 0.2 2.2 3 7 DMSO 55% 72 4.0  8% P0.6R2 0.6 1.9 13 26 32%dP0.2R13 0.2 13.0 3 39 DMSO 55% 73 4.0  8% P0.6R2 0.6 1.9 13 26 32%dP0.4R2 0.4 2.0 7 14 DMSO 55% 74 4.0  8% P0.6R2 0.6 1.9 13 26 32%dP0.4R8 0.4 8.4 7 61 DMSO 55% 75 4.0  8% P0.6R2 0.6 1.9 13 26 32%dP0.6R3 0.6 3.0 12 35 DMSO 55% 76 4.0  8% P0.6R2 0.6 1.9 13 26 32%dP0.6R5 0.6 5.1 12 60 DMSO 55% 77 4.0  8% P0.6R2 0.6 1.9 13 26 32% dP1R31.0 3.0 22 66 DMSO 55% 78 4.0  8% P0.6R2 0.6 1.9 13 26 32% dP1R5 1.0 5.422 119 DMSO 55% 79 4.0  8% P0.6R2 0.6 1.9 13 26 32% dP2R1 2.0 1.3 45 58DMSO 55% 80 4.0  8% P0.6R2 0.6 1.9 13 26 32% dP2R5 2.0 5.3 45 237 DMSO55% 81 4.0  8% P0.6R4 0.6 4.2 13 55 32% dP0.2R2 0.2 2.2 3 7 DMSO 55% 824.0  8% P0.6R4 0.6 4.2 13 55 32% dP0.2R13 0.2 13.0 3 39 DMSO 55% 83 4.0 8% P0.6R4 0.6 4.2 13 55 32% dP0.4R2 0.4 2.0 7 14 DMSO 55% 84 4.0  8%P0.6R4 0.6 4.2 13 55 32% dP0.4R8 0.4 8.4 7 61 DMSO 55% 85 4.0  8% P0.6R40.6 4.2 13 55 32% dP0.6R3 0.6 3.0 12 35 DMSO 55% 86 4.0  8% P0.6R4 0.64.2 13 55 32% dP0.6R5 0.6 5.1 12 60 DMSO 55% 87 4.0  8% P0.6R4 0.6 4.213 55 32% dP1R3 1.0 3.0 22 66 DMSO 55% 88 4.0  8% P0.6R4 0.6 4.2 13 5532% dP1R5 1.0 5.4 22 119 DMSO 55% 89 4.0  8% P0.6R4 0.6 4.2 13 55 32%dP2R1 2.0 1.3 45 58 DMSO 55% 90 4.0  8% P0.6R4 0.6 4.2 13 55 32% dP2R52.0 5.3 45 237 DMSO 55% 91 4.0  8% P1R2 1.0 2.1 22 47 32% dP0.2R2 0.22.2 3 7 DMSO 55% 92 4.0  8% P1R2 1.0 2.1 22 47 32% dP0.2R13 0.2 13.0 339 DMSO 55% 93 4.0  8% P1R2 1.0 2.1 22 47 32% dP0.4R2 0.4 2.0 7 14 DMSO55% 94 4.0  8% P1R2 1.0 2.1 22 47 32% dP0.4R8 0.4 8.4 7 61 DMSO 55% 954.0  8% P1R2 1.0 2.1 22 47 32% dP0.6R3 0.6 3.0 12 35 DMSO 55% 96 4.0  8%P1R2 1.0 2.1 22 47 32% dP0.6R5 0.6 5.1 12 60 DMSO 55% 97 4.0  8% P1R21.0 2.1 22 47 32% dP1R3 1.0 3.0 22 66 DMSO 55% 98 4.0  8% P1R2 1.0 2.122 47 32% dP1R5 1.0 5.4 22 119 DMSO 55% 99 4.0  8% P1R2 1.0 2.1 22 4732% dP2R1 2.0 1.3 45 58 DMSO 55% 100 4.0  8% P1R2 1.0 2.1 22 47 32%dP2R5 2.0 5.3 45 237 DMSO 55% 101 4.0  8% PIR4 1.0 4.0 22 88 32% dP0.2R20.2 2.2 3 7 DMSO 55% 102 4.0  8% PIR4 1.0 4.0 22 88 32% dP0.2R13 0.213.0 3 39 DMSO 55% 103 4.0  8% P1R4 1.0 4.0 22 88 32% dP0.4R2 0.4 2.0 714 DMSO 55% 104 4.0  8% P1R4 1.0 4.0 22 88 32% dP0.4R8 0.4 8.4 7 61 DMSO55% 105 4.0  8% P1R4 1.0 4.0 22 88 32% dP0.6R3 0.6 3.0 12 35 DMSO 55%106 4.0  8% P1R4 1.0 4.0 22 88 32% dP0.6R5 0.6 5.1 12 60 DMSO 55% 1074.0  8% P1R4 1.0 4.0 22 88 32% dP1R3 1.0 3.0 22 66 DMSO 55% 108 4.0  8%P1R4 1.0 4.0 22 88 32% dP1R5 1.0 5.4 22 119 DMSO 55% 109 4.0  8% P1R41.0 4.0 22 88 32% dP2R1 2.0 1.3 45 58 DMSO 55% 110 4.0  8% P1R4 1.0 4.022 88 32% dP2R5 2.0 5.3 45 237 DMSO 55% 111 4.0  8% P2R2 2.0 2.0 45 8832% dP0.2R2 0.2 2.2 3 7 DMSO 55% 112 4.0  8% P2R2 2.0 2.0 45 88 32%dP0.2R13 0.2 13.0 3 39 DMSO 55% 113 4.0  8% P2R2 2.0 2.0 45 88 32%dP0.4R2 0.4 2.0 7 14 DMSO 55% 114 4.0  8% P2R2 2.0 2.0 45 88 32% dP0.4R80.4 8.4 7 61 DMSO 55% 115 4.0  8% P2R2 2.0 2.0 45 88 32% dP0.6R3 0.6 3.012 35 DMSO 55% 116 4.0  8% P2R2 2.0 2.0 45 88 32% dP0.6R5 0.6 5.1 12 60DMSO 55% 117 4.0  8% P2R2 2.0 2.0 45 88 32% dP1R3 1.0 3.0 22 66 DMSO 55%118 4.0  8% P2R2 2.0 2.0 45 88 32% dP1R5 1.0 5.4 22 119 DMSO 55% 119 4.0 8% P2R2 2.0 2.0 45 88 32% dP2R1 2.0 1.3 45 58 DMSO 55% 120 4.0  8% P2R22.0 2.0 45 88 32% dP2R5 2.0 5.3 45 237 DMSO 55% 121 4.0  8% P2R5 2.0 4.845 216 32% dP0.2R2 0.2 2.2 3 7 DMSO 55% 122 4.0  8% P2R5 2.0 4.8 45 21632% dP0.2R13 0.2 13.0 3 39 DMSO 55% 123 4.0  8% P2R5 2.0 4.8 45 216 32%dP0.4R2 0.4 2.0 7 14 DMSO 55% 124 4.0  8% P2R5 2.0 4.8 45 216 32%dP0.4R8 0.4 8.4 7 61 DMSO 55% 125 4.0  8% P2R5 2.0 4.8 45 216 32%dP0.6R3 0.6 3.0 12 35 DMSO 55% 126 4.0  8% P2R5 2.0 4.8 45 216 32%dP0.6R5 0.6 5.1 12 60 DMSO 55% 127 4.0  8% P2R5 2.0 4.8 45 216 32% dP1R31.0 3.0 22 66 DMSO 55% 128 4.0  8% P2R5 2.0 4.8 45 216 32% dP1R5 1.0 5.422 119 DMSO 55% 129 4.0  8% P2R5 2.0 4.8 45 216 32% dP2R1 2.0 1.3 45 58DMSO 55% 130 4.0  8% P2R5 2.0 4.8 45 216 32% dP2R5 2.0 5.3 45 237 DMSO55% 131 4.0  8% P3R1 3.0 1.0 68 66 32% dP0.2R2 0.2 2.2 3 7 DMSO 55% 1324.0  8% P3R1 3.0 1.0 68 66 32% dP0.2R13 0.2 13.0 3 39 DMSO 55% 133 4.0 8% P3R1 3.0 1.0 68 66 32% dP0.4R2 0.4 2.0 7 14 DMSO 55% 134 4.0  8%P3R1 3.0 1.0 68 66 32% dP0.4R8 0.4 8.4 7 61 DMSO 55% 135 4.0  8% P3R13.0 1.0 68 66 32% dP0.6R3 0.6 3.0 12 35 DMSO 55% 136 4.0  8% P3R1 3.01.0 68 66 32% dP0.6R5 0.6 5.1 12 60 DMSO 55% 137 4.0  8% P3R1 3.0 1.0 6866 32% dP1R3 1.0 3.0 22 66 DMSO 55% 138 4.0  8% P3R1 3.0 1.0 68 66 32%dP1R5 1.0 5.4 22 119 DMSO 55% 139 4.0  8% P3R1 3.0 1.0 68 66 32% dP2R12.0 1.3 45 58 DMSO 55% 140 4.0  8% P3R1 3.0 1.0 68 66 32% dP2R5 2.0 5.345 237 DMSO 55% 141 4.0  8% P3R3 3.0 3.2 68 218 32% dP0.2R2 0.2 2.2 3 7DMSO 55% 142 4.0  8% P3R3 3.0 3.2 68 218 32% dP0.2R13 0.2 13.0 3 39 DMSO55% 143 4.0  8% P3R3 3.0 3.2 68 218 32% dP0.4R2 0.4 2.0 7 14 DMSO 55%144 4.0  8% P3R3 3.0 3.2 68 218 32% dP0.4R8 0.4 8.4 7 61 DMSO 55% 1454.0  8% P3R3 3.0 3.2 68 218 32% dP0.6R3 0.6 3.0 12 35 DMSO 55% 146 4.0 8% P3R3 3.0 3.2 68 218 32% dP0.6R5 0.6 5.1 12 60 DMSO 55% 147 4.0  8%P3R3 3.0 3.2 68 218 32% dP1R3 1.0 3.0 22 66 DMSO 55% 148 4.0  8% P3R33.0 3.2 68 218 32% dP1R5 1.0 5.4 22 119 DMSO 55% 149 4.0  8% P3R3 3.03.2 68 218 32% dP2R1 2.0 1.3 45 58 DMSO 55% 150 4.0  8% P3R3 3.0 3.2 68218 32% dP2R5 2.0 5.3 45 237 DMSO 55% 151 4.0  8% P6R0.9 6.0 0.9 136 12532% dP0.2R2 0.2 2.2 3 7 DMSO 55% 152 4.0  8% P6R0.9 6.0 0.9 136 125 32%dP0.2R13 0.2 13.0 3 39 DMSO 55% 153 4.0  8% P6R0.9 6.0 0.9 136 125 32%dP0.4R2 0.4 2.0 7 14 DMSO 55% 154 4.0  8% P6R0.9 6.0 0.9 136 125 32%dP0.4R8 0.4 8.4 7 61 DMSO 55% 155 4.0  8% P6R0.9 6.0 0.9 136 125 32%dP0.6R3 0.6 3.0 12 35 DMSO 55% 156 4.0  8% P6R0.9 6.0 0.9 136 125 32%dP0.6R5 0.6 5.1 12 60 DMSO 55% 157 4.0  8% P6R0.9 6.0 0.9 136 125 32%dP1R3 1.0 3.0 22 66 DMSO 55% 158 4.0  8% P6R0.9 6.0 0.9 136 125 32%dP1R5 1.0 5.4 22 119 DMSO 55% 159 4.0  8% P6R0.9 6.0 0.9 136 125 32%dP2R1 2.0 1.3 45 58 DMSO 55% 160 4.0  8% P6R0.9 6.0 0.9 136 125 32%dP2R5 2.0 5.3 45 237 DMSO 55% 161 4.0  8% P6R2 6.0 2.0 136 272 32%dP0.2R2 0.2 2.2 3 7 DMSO 55% 162 4.0  8% P6R2 6.0 2.0 136 272 32%dP0.2R13 0.2 13.0 3 39 DMSO 55% 163 4.0  8% P6R2 6.0 2.0 136 272 32%dP0.4R2 0.4 2.0 7 14 DMSO 55% 164 4.0  8% P6R2 6.0 2.0 136 272 32%dP0.4R8 0.4 8.4 7 61 DMSO 55% 165 4.0  8% P6R2 6.0 2.0 136 272 32%dP0.6R3 0.6 3.0 12 35 DMSO 55% 166 4.0  8% P6R2 6.0 2.0 136 272 32%dP0.6R5 0.6 5.1 12 60 DMSO 55% 167 4.0  8% P6R2 6.0 2.0 136 272 32%dP1R3 1.0 3.0 22 66 DMSO 55% 168 4.0  8% P6R2 6.0 2.0 136 272 32% dP1R51.0 5.4 22 119 DMSO 55% 169 4.0  8% P6R2 6.0 2.0 136 272 32% dP2R1 2.01.3 45 58 DMSO 55% 170 4.0  8% P6R2 6.0 2.0 136 272 32% dP2R5 2.0 5.3 45237 DMSO 55% 171 4.0  8% P0.2R6 0.2 5.9 4 24 32% dP0.2R6 0.2 5.8 3 17DMSO 55% 172 4.0  8% P0.2R6 0.2 5.9 4 24 32% dP0.4R6 0.4 5.8 7 42 DMSO55% 173 4.0  8% P0.2R6 0.2 5.9 4 24 32% dP0.6R5 0.6 4.6 12 54 DMSO 55%174 4.0  8% P0.2R6 0.2 5.9 4 24 32% dP1R4 1.0 4.0 22 89 DMSO 55% 175 4.0 8% P0.2R6 0.2 5.9 4 24 32% dP2R3 2.0 2.8 45 125 DMSO 55% 176 4.0  8%P0.2R22 0.2 22.3 4 89 32% dP0.2R6 0.2 5.8 3 17 DMSO 55% 177 4.0  8%P0.2R22 0.2 22.3 4 89 32% dP0.4R6 0.4 5.8 7 42 DMSO 55% 178 4.0  8%P0.2R22 0.2 22.3 4 89 32% dP0.6R5 0.6 4.6 12 54 DMSO 55% 179 4.0  8%P0.2R22 0.2 22.3 4 89 32% dP1R4 1.0 4.0 22 89 DMSO 55% 180 4.0  8%P0.2R22 0.2 22.3 4 89 32% dP2R3 2.0 2.8 45 125 DMSO 55% 181 4.0  8%P0.4R5 0.4 4.7 9 41 32% dP0.2R6 0.2 5.8 3 17 DMSO 55% 182 4.0  8% P0.4R50.4 4.7 9 41 32% dP0.4R6 0.4 5.8 7 42 DMSO 55% 183 4.0  8% P0.4R5 0.44.7 9 41 32% dP0.6R5 0.6 4.6 12 54 DMSO 55% 184 4.0  8% P0.4R5 0.4 4.7 941 32% dP1R4 1.0 4.0 22 89 DMSO 55% 185 4.0  8% P0.4R5 0.4 4.7 9 41 32%dP2R3 2.0 2.8 45 125 DMSO 55% 186 4.0  8% P0.4R8 0.4 7.7 9 67 32%dP0.2R6 0.2 5.8 3 17 DMSO 55% 187 4.0  8% P0.4R8 0.4 7.7 9 67 32%dP0.4R6 0.4 5.8 7 42 DMSO 55% 188 4.0  8% P0.4R8 0.4 7.7 9 67 32%dP0.6R5 0.6 4.6 12 54 DMSO 55% 189 4.0  8% P0.4R8 0.4 7.7 9 67 32% dP1R41.0 4.0 22 89 DMSO 55% 190 4.0  8% P0.4R8 0.4 7.7 9 67 32% dP2R3 2.0 2.845 125 DMSO 55% 191 4.0  8% P0.6R2 0.6 1.9 13 26 32% dP0.2R6 0.2 5.8 317 DMSO 55% 192 4.0  8% P0.6R2 0.6 1.9 13 26 32% dP0.4R6 0.4 5.8 7 42DMSO 55% 193 4.0  8% P0.6R2 0.6 1.9 13 26 32% dP0.6R5 0.6 4.6 12 54 DMSO55% 194 4.0  8% P0.6R2 0.6 1.9 13 26 32% dP1R4 1.0 4.0 22 89 DMSO 55%195 4.0  8% P0.6R2 0.6 1.9 13 26 32% dP2R3 2.0 2.8 45 125 DMSO 55% 1964.0  8% P0.6R4 0.6 4.2 13 55 32% dP0.2R6 0.2 5.8 3 17 DMSO 55% 197 4.0 8% P0.6R4 0.6 4.2 13 55 32% dP0.4R6 0.4 5.8 7 42 DMSO 55% 198 4.0  8%P0.6R4 0.6 4.2 13 55 32% dP0.6R5 0.6 4.6 12 54 DMSO 55% 199 4.0  8%P0.6R4 0.6 4.2 13 55 32% dP1R4 1.0 4.0 22 89 DMSO 55% 200 4.0  8% P0.6R40.6 4.2 13 55 32% dP2R3 2.0 2.8 45 125 DMSO 55% 201 4.0  8% P1R2 1.0 2.122 47 32% dP0.2R6 0.2 5.8 3 17 DMSO 55% 202 4.0  8% P1R2 1.0 2.1 22 4732% dP0.4R6 0.4 5.8 7 42 DMSO 55% 203 4.0  8% P1R2 1.0 2.1 22 47 32%dP0.6R5 0.6 4.6 12 54 DMSO 55% 204 4.0  8% P1R2 1.0 2.1 22 47 32% dP1R41.0 4.0 22 89 DMSO 55% 205 4.0  8% P1R2 1.0 2.1 22 47 32% dP2R3 2.0 2.845 125 DMSO 55% 206 4.0  8% P1R4 1.0 4.0 22 88 32% dP0.2R6 0.2 5.8 3 17DMSO 55% 207 4.0  8% P1R4 1.0 4.0 22 88 32% dP0.4R6 0.4 5.8 7 42 DMSO55% 208 4.0  8% P1R4 1.0 4.0 22 88 32% dP0.6R5 0.6 4.6 12 54 DMSO 55%209 4.0  8% P1R4 1.0 4.0 22 88 32% dP1R4 1.0 4.0 22 89 DMSO 55% 210 4.0 8% P1R4 1.0 4.0 22 88 32% dP2R3 2.0 2.8 45 125 DMSO 55% 211 4.0  8%P2R2 2.0 2.0 45 88 32% dP0.2R6 0.2 5.8 3 17 DMSO 55% 212 4.0  8% P2R22.0 2.0 45 88 32% dP0.4R6 0.4 5.8 7 42 DMSO 55% 213 4.0  8% P2R2 2.0 2.045 88 32% dP0.6R5 0.6 4.6 12 54 DMSO 55% 214 4.0  8% P2R2 2.0 2.0 45 8832% dP1R4 1.0 4.0 22 89 DMSO 55% 215 4.0  8% P2R2 2.0 2.0 45 88 32%dP2R3 2.0 2.8 45 125 DMSO 55% 216 4.0  8% P2R5 2.0 4.8 45 216 32%dP0.2R6 0.2 5.8 3 17 DMSO 55% 217 4.0  8% P2R5 2.0 4.8 45 216 32%dP0.4R6 0.4 5.8 7 42 DMSO 55% 218 4.0  8% P2R5 2.0 4.8 45 216 32%dP0.6R5 0.6 4.6 12 54 DMSO 55% 219 4.0  8% P2R5 2.0 4.8 45 216 32% dP1R41.0 4.0 22 89 DMSO 55% 220 4.0  8% P2R5 2.0 4.8 45 216 32% dP2R3 2.0 2.845 125 DMSO 55% 221 4.0  8% P3R1 3.0 1.0 68 66 32% dP0.2R6 0.2 5.8 3 17DMSO 55% 222 4.0  8% P3R1 3.0 1.0 68 66 32% dP0.4R6 0.4 5.8 7 42 DMSO55% 223 4.0  8% P3R1 3.0 1.0 68 66 32% dP0.6R5 0.6 4.6 12 54 DMSO 55%224 4.0  8% P3R1 3.0 1.0 68 66 32% dP1R4 1.0 4.0 22 89 DMSO 55% 225 4.0 8% P3R1 3.0 1.0 68 66 32% dP2R3 2.0 2.8 45 125 DMSO 55% 226 4.0  8%P3R3 3.0 3.2 68 218 32% dP0.2R6 0.2 5.8 3 17 DMSO 55% 227 4.0  8% P3R33.0 3.2 68 218 32% dP0.4R6 0.4 5.8 7 42 DMSO 55% 228 4.0  8% P3R3 3.03.2 68 218 32% dP0.6R5 0.6 4.6 12 54 DMSO 55% 229 4.0  8% P3R3 3.0 3.268 218 32% dP1R4 1.0 4.0 22 89 DMSO 55% 230 4.0  8% P3R3 3.0 3.2 68 21832% dP2R3 2.0 2.8 45 125 DMSO 55% 231 4.0  8% P6R0.9 6.0 0.9 136 125 32%dP0.2R6 0.2 5.8 3 17 DMSO 55% 232 4.0  8% P6R0.9 6.0 0.9 136 125 32%dP0.4R6 0.4 5.8 7 42 DMSO 55% 233 4.0  8% P6R0.9 6.0 0.9 136 125 32%dP0.6R5 0.6 4.6 12 54 DMSO 55% 234 4.0  8% P6R0.9 6.0 0.9 136 125 32%dP1R4 1.0 4.0 22 89 DMSO 55% 235 4.0  8% P6R0.9 6.0 0.9 136 125 32%dP2R3 2.0 2.8 45 125 DMSO 55% 236 4.0  8% P6R2 6.0 2.0 136 272 32%dP0.2R6 0.2 5.8 3 17 DMSO 55% 237 4.0  8% P6R2 6.0 2.0 136 272 32%dP0.4R6 0.4 5.8 7 42 DMSO 55% 238 4.0  8% P6R2 6.0 2.0 136 272 32%dP0.6R5 0.6 4.6 12 54 DMSO 55% 239 4.0  8% P6R2 6.0 2.0 136 272 32%dP1R4 1.0 4.0 22 89 DMSO 55% 240 4.0  8% P6R2 6.0 2.0 136 272 32% dP2R32.0 2.8 45 125 DMSO 55% 241 4.0  8% P0.2R14 0.2 14.5 4 58 32% dP0.2R20.2 2.2 3 7 DMSO 55% 242 4.0  8% P0.2R14 0.2 14.5 4 58 32% dP0.2R13 0.213.0 3 39 DMSO 55% 243 4.0  8% P0.2R14 0.2 14.5 4 58 32% dP0.4R2 0.4 2.07 14 DMSO 55% 244 4.0  8% P0.2R14 0.2 14.5 4 58 32% dP0.4R8 0.4 8.4 7 61DMSO 55% 245 4.0  8% P0.2R14 0.2 14.5 4 58 32% dP0.6R3 0.6 3.0 12 35DMSO 55% 246 4.0  8% P0.2R14 0.2 14.5 4 58 32% dP0.6R5 0.6 5.1 12 60DMSO 55% 247 4.0  8% P0.2R14 0.2 14.5 4 58 32% dP1R3 1.0 3.0 22 66 DMSO55% 248 4.0  8% P0.2R14 0.2 14.5 4 58 32% dP1R5 1.0 5.4 22 119 DMSO 55%249 4.0  8% P0.2R14 0.2 14.5 4 58 32% dP2R1 2.0 1.3 45 58 DMSO 55% 2504.0  8% P0.2R14 0.2 14.5 4 58 32% dP2R5 2.0 5.3 45 237 DMSO 55% 251 4.0 8% P0.6R3 0.6 3.0 13 40 32% dP0.2R2 0.2 2.2 3 7 DMSO 55% 252 4.0  8%P0.6R3 0.6 3.0 13 40 32% dP0.2R13 0.2 13.0 3 39 DMSO 55% 253 4.0  8%P0.6R3 0.6 3.0 13 40 32% dP0.4R2 0.4 2.0 7 14 DMSO 55% 254 4.0  8%P0.6R3 0.6 3.0 13 40 32% dP0.4R8 0.4 8.4 7 61 DMSO 55% 255 4.0  8%P0.6R3 0.6 3.0 13 40 32% dP0.6R3 0.6 3.0 12 35 DMSO 55% 256 4.0  8%P0.6R3 0.6 3.0 13 40 32% dP0.6R5 0.6 5.1 12 60 DMSO 55% 257 4.0  8%P0.6R3 0.6 3.0 13 40 32% dP1R3 1.0 3.0 22 66 DMSO 55% 258 4.0  8% P0.6R30.6 3.0 13 40 32% dP1R5 1.0 5.4 22 119 DMSO 55% 259 4.0  8% P0.6R3 0.63.0 13 40 32% dP2R1 2.0 1.3 45 58 DMSO 55% 260 4.0  8% P0.6R3 0.6 3.0 1340 32% dP2R5 2.0 5.3 45 237 DMSO 55% 261 4.0  8% P1R3 1.0 3.1 22 68 32%dP0.2R2 0.2 2.2 3 7 DMSO 55% 262 4.0  8% P1R3 1.0 3.1 22 68 32% dP0.2R130.2 13.0 3 39 DMSO 55% 263 4.0  8% P1R3 1.0 3.1 22 68 32% dP0.4R2 0.42.0 7 14 DMSO 55% 264 4.0  8% P1R3 1.0 3.1 22 68 32% dP0.4R8 0.4 8.4 761 DMSO 55% 265 4.0  8% P1R3 1.0 3.1 22 68 32% dP0.6R3 0.6 3.0 12 35DMSO 55% 266 4.0  8% P1R3 1.0 3.1 22 68 32% dP0.6R5 0.6 5.1 12 60 DMSO55% 267 4.0  8% P1R3 1.0 3.1 22 68 32% dP1R3 1.0 3.0 22 66 DMSO 55% 2684.0  8% P1R3 1.0 3.1 22 68 32% dP1R5 1.0 5.4 22 119 DMSO 55% 269 4.0  8%P1R3 1.0 3.1 22 68 32% dP2R1 2.0 1.3 45 58 DMSO 55% 270 4.0  8% P1R3 1.03.1 22 68 32% dP2R5 2.0 5.3 45 237 DMSO 55% 271 4.0  8% P2R3 2.0 3.5 45157 32% dP0.2R2 0.2 2.2 3 7 DMSO 55% 272 4.0  8% P2R3 2.0 3.5 45 157 32%dP0.2R13 0.2 13.0 3 39 DMSO 55% 273 4.0  8% P2R3 2.0 3.5 45 157 32%dP0.4R2 0.4 2.0 7 14 DMSO 55% 274 4.0  8% P2R3 2.0 3.5 45 157 32%dP0.4R8 0.4 8.4 7 61 DMSO 55% 275 4.0  8% P2R3 2.0 3.5 45 157 32%dP0.6R3 0.6 3.0 12 35 DMSO 55% 276 4.0  8% P2R3 2.0 3.5 45 157 32%dP0.6R5 0.6 5.1 12 60 DMSO 55% 277 4.0  8% P2R3 2.0 3.5 45 157 32% dP1R31.0 3.0 22 66 DMSO 55% 278 4.0  8% P2R3 2.0 3.5 45 157 32% dP1R5 1.0 5.422 119 DMSO 55% 279 4.0  8% P2R3 2.0 3.5 45 157 32% dP2R1 2.0 1.3 45 58DMSO 55% 280 4.0  8% P2R3 2.0 3.5 45 157 32% dP2R5 2.0 5.3 45 237 DMSO55% 281 4.0  8% P3R2 3.0 2.3 68 154 32% dP0.2R2 0.2 2.2 3 7 DMSO 55% 2824.0  8% P3R2 3.0 2.3 68 154 32% dP0.2R13 0.2 13.0 3 39 DMSO 55% 283 4.0 8% P3R2 3.0 2.3 68 154 32% dP0.4R2 0.4 2.0 7 14 DMSO 55% 284 4.0  8%P3R2 3.0 2.3 68 154 32% dP0.4R8 0.4 8.4 7 61 DMSO 55% 285 4.0  8% P3R23.0 2.3 68 154 32% dP0.6R3 0.6 3.0 12 35 DMSO 55% 286 4.0  8% P3R2 3.02.3 68 154 32% dP0.6R5 0.6 5.1 12 60 DMSO 55% 287 4.0  8% P3R2 3.0 2.368 154 32% dP1R3 1.0 3.0 22 66 DMSO 55% 288 4.0  8% P3R2 3.0 2.3 68 15432% dP1R5 1.0 5.4 22 119 DMSO 55% 289 4.0  8% P3R2 3.0 2.3 68 154 32%dP2R1 2.0 1.3 45 58 DMSO 55% 290 4.0  8% P3R2 3.0 2.3 68 154 32% dP2R52.0 5.3 45 237 DMSO 55% 291 4.0  8% P6R2 6.0 1.6 136 218 32% dP0.2R2 0.22.2 3 7 DMSO 55% 292 4.0  8% P6R2 6.0 1.6 136 218 32% dP0.2R13 0.2 13.03 39 DMSO 55% 293 4.0  8% P6R2 6.0 1.6 136 218 32% dP0.4R2 0.4 2.0 7 14DMSO 55% 294 4.0  8% P6R2 6.0 1.6 136 218 32% dP0.4R8 0.4 8.4 7 61 DMSO55% 295 4.0  8% P6R2 6.0 1.6 136 218 32% dP0.6R3 0.6 3.0 12 35 DMSO 55%296 4.0  8% P6R2 6.0 1.6 136 218 32% dP0.6R5 0.6 5.1 12 60 DMSO 55% 2974.0  8% P6R2 6.0 1.6 136 218 32% dP1R3 1.0 3.0 22 66 DMSO 55% 298 4.0 8% P6R2 6.0 1.6 136 218 32% dP1R5 1.0 5.4 22 119 DMSO 55% 299 4.0  8%P6R2 6.0 1.6 136 218 32% dP2R1 2.0 1.3 45 58 DMSO 55% 300 4.0  8% P6R26.0 1.6 136 218 32% dP2R5 2.0 5.3 45 237 DMSO 55% 301 0.0 40% P2R3 2.03.5 45 157  0% dP0.4R6 0.4 5.8 7 42 DMSO 55% 302 0.05 38% P2R3 2.0 3.545 157  2% dP0.4R6 0.4 5.8 7 42 DMSO 55% 303 0.11 36% P2R3 2.0 3.5 45157  4% dP0.4R6 0.4 5.8 7 42 DMSO 55% 304 0.25 32% P2R3 2.0 3.5 45 157 8% dP0.4R6 0.4 5.8 7 42 DMSO 55% 305 1.00 20% P2R3 2.0 3.5 45 157 20%dP0.4R6 0.4 5.8 7 42 DMSO 55% 306 4.0  8% P2R3 2.0 3.5 45 157 32%dP0.4R6 0.4 5.8 7 42 DMSO 55% 307 9.0  4% P2R3 2.0 3.5 45 157 36%dP0.4R6 0.4 5.8 7 42 DMSO 55% 308 19.0  2% P2R3 2.0 3.5 45 157 38%dP0.4R6 0.4 5.8 7 42 DMSO 55% 309 ∞  0% P2R3 2.0 3.5 45 157 40% dP0.4R60.4 5.8 7 42 DMSO 55% 310 0.0 40% P2R3 2.0 3.5 45 157  0% dP0.6R5 0.64.6 12 54 DMSO 55% 311 0.05 38% P2R3 2.0 3.5 45 157  2% dP0.6R5 0.6 4.612 54 DMSO 55% 312 0.11 36% P2R3 2.0 3.5 45 157  4% dP0.6R5 0.6 4.6 1254 DMSO 55% 313 0.25 32% P2R3 2.0 3.5 45 157  8% dP0.6R5 0.6 4.6 12 54DMSO 55% 314 1.00 20% P2R3 2.0 3.5 45 157 20% dP0.6R5 0.6 4.6 12 54 DMSO55% 315 4.0  8% P2R3 2.0 3.5 45 157 32% dP0.6R5 0.6 4.6 12 54 DMSO 55%316 9.0  4% P2R3 2.0 3.5 45 157 36% dP0.6R5 0.6 4.6 12 54 DMSO 55% 31719.0  2% P2R3 2.0 3.5 45 157 38% dP0.6R5 0.6 4.6 12 54 DMSO 55% 318 ∞ 0% P2R3 2.0 3.5 45 157 40% dP0.6R5 0.6 4.6 12 54 DMSO 55% 319 0.0 40%P0.4R8 0.4 7.7 9 67  0% dP0.4R8 0.4 8.4 7 61 DMSO 55% 320 0.05 38%P0.4R8 0.4 7.7 9 67  2% dP0.4R8 0.4 8.4 7 61 DMSO 55% 321 0.11 36%P0.4R8 0.4 7.7 9 67  4% dP0.4R8 0.4 8.4 7 61 DMSO 55% 322 0.25 32%P0.4R8 0.4 7.7 9 67  8% dP0.4R8 0.4 8.4 7 61 DMSO 55% 323 1.00 20%P0.4R8 0.4 7.7 9 67 20% dP0.4R8 0.4 8.4 7 61 DMSO 55% 324 4.0  8% P0.4R80.4 7.7 9 67 32% dP0.4R8 0.4 8.4 7 61 DMSO 55% 325 9.0  4% P0.4R8 0.47.7 9 67 36% dP0.4R8 0.4 8.4 7 61 DMSO 55% 326 19.0  2% P0.4R8 0.4 7.7 967 38% dP0.4R8 0.4 8.4 7 61 DMSO 55% 327 ∞  0% P0.4R8 0.4 7.7 9 67 40%dP0.4R8 0.4 8.4 7 61 DMSO 55% 328 0.0 40% P1R2 1.0 2.1 22 47  0% dP0.6R50.6 5.1 12 60 DMSO 55% 329 0.05 38% P1R2 1.0 2.1 22 47  2% dP0.6R5 0.65.1 12 60 DMSO 55% 330 0.11 36% P1R2 1.0 2.1 22 47  4% dP0.6R5 0.6 5.112 60 DMSO 55% 331 0.25 32% P1R2 1.0 2.1 22 47  8% dP0.6R5 0.6 5.1 12 60DMSO 55% 332 1.00 20% P1R2 1.0 2.1 22 47 20% dP0.6R5 0.6 5.1 12 60 DMSO55% 333 4.0  8% P1R2 1.0 2.1 22 47 32% dP0.6R5 0.6 5.1 12 60 DMSO 55%334 9.0  4% P1R2 1.0 2.1 22 47 36% dP0.6R5 0.6 5.1 12 60 DMSO 55% 33519.0  2% P1R2 1.0 2.1 22 47 38% dP0.6R5 0.6 5.1 12 60 DMSO 55% 336 ∞  0%P1R2 1.0 2.1 22 47 40% dP0.6R5 0.6 5.1 12 60 DMSO 55% 337 0.0 40% P2R52.0 4.8 45 216  0% dP0.2R13 0.2 13.0 3 39 DMSO 55% 338 0.05 38% P2R5 2.04.8 45 216  2% dP0.2R13 0.2 13.0 3 39 DMSO 55% 339 0.11 36% P2R5 2.0 4.845 216  4% dP0.2R1 0.2 13.0 3 39 DMSO 55% 340 0.25 32% P2R5 2.0 4.8 45216  8% dP0.2R13 0.2 13.0 3 39 DMSO 55% 341 1.00 20% P2R5 2.0 4.8 45 21620% dP0.2R13 0.2 13.0 3 39 DMSO 55% 342 4.0  8% P2R5 2.0 4.8 45 216 32%dP0.2R13 0.2 13.0 3 39 DMSO 55% 343 9.0  4% P2R5 2.0 4.8 45 216 36%dP0.2R13 0.2 13.0 3 39 DMSO 55% 344 19.0  2% P2R5 2.0 4.8 45 216 38%dP0.2R13 0.2 13.0 3 39 DMSO 55% 345 ∞  0% P2R5 2.0 4.8 45 216 40%dP0.2R13 0.2 13.0 3 39 DMSO 55%

Example 5—Buprenorphine's Formulations Preparation

The formulations described herein were based on organic solution ofpolymers prepared as in Example 1, containing as the drug,buprenorphine. Typically, 0.4 grams of polymers, corresponding to a mixof a diblock copolymer and a triblock copolymer in defined mass ratio,were dissolved in 0.5 grams of dimethyl sulfoxide at room temperatureovernight under constant magnetic stirring. The next day, 100 mg ofbuprenorphine was added to the polymer solution and stirred untilcomplete dissolution. The formulations were loaded in syringe beforeuse.

Three different formulations were selected for in vivo experiments. Thecomposition of these formulations is shown in Table 3 below. Theformulations were injected subcutaneously in the interscapular space ofmale rats (200-250 gr) at a final dose of 100 mg/kg of buprenorphine.Blood samples were withdraw periodically and analyzed for buprenorphineconcentrations by LC/MS/MS.

The formulations are shown in Table 3 below.

TABLE 3 Triblock copolymer (TB) Diblock copolymer (DB) Ratio RatioSolvent Exp Ratio % PEG (LA/ DP- DP- % PEG (LA/ DP- DP- % no DB/TB (w/w)Code (kDa) EO) PEG PLA (w/w) Code (kDa) EO) PEG PLA Name (w/w) 1 4.010.0% P0.4R8 0.4 7.7 9 70 40.0% dP0.4R10 0.35 9.8 8 78 DMSO 40.0% 2 4.010.0% P2R2 2 2.2 45 101 40.0% dP0.4R10 0.35 9.8 8 78 DMSO 40.0% 3 4.010.0% P2R3 2 3.3 45 150 40.0% dP0.4R10 0.35 9.8 8 78 DMSO 40.0% 4 4.010.0% P2R4 2 4.3 45 195 40.0% dP0.4R10 0.35 9.8 8 78 DMSO 40.0% 5 4.010.0% P0.4R8 0.4 7.7 9 70 40.0% dP1R4 1 4.2 23 95 DMSO 40.0% 6 4.0 10.0%P2R2 2 2.2 45 101 40.0% dP1R4 1 4.2 23 95 DMSO 40.0% 7 4.0 10.0% P2R3 23.3 45 150 40.0% dP1R4 1 4.2 23 95 DMSO 40.0% 8 4.0 10.0% P2R4 2 4.3 45195 40.0% dP1R4 1 4.2 23 95 DMSO 40.0% 9 4.0 10.0% P0.4R8 0.4 7.7 9 7040.0% dP1R5 1 5.4 23 123 DMSO 40.0% 10 4.0 10.0% P2R2 2 2.2 45 101 40.0%dP1R5 1 5.4 23 123 DMSO 40.0% 11 4.0 10.0% P2R3 2 3.3 45 150 40.0% dP1R51 5.4 23 123 DMSO 40.0% 12 4.0 10.0% P2R4 2 4.3 45 195 40.0% dP1R5 1 5.423 123 DMSO 40.0% 13 4.0 10.0% P0.4R8 0.4 7.7 9 70 40.0% dP2R3 2 2.7 45120 DMSO 40.0% 14 4.0 10.0% P2R2 2 2.2 45 101 40.0% dP2R3 2 2.7 45 120DMSO 40.0% 15 4.0 10.0% P2R3 2 3.3 45 150 40.0% dP2R3 2 2.7 45 120 DMSO40.0% 16 4.0 10.0% P2R4 2 4.3 45 195 40.0% dP2R3 2 2.7 45 120 DMSO 40.0%17 4.0 10.0% P0.4R8 0.4 7.7 9 70 40.0% dP2R4 2 4.1 45 186 DMSO 40.0% 184.0 10.0% P2R2 2 2.2 45 101 40.0% dP2R4 2 4.1 45 186 DMSO 40.0% 19 4.010.0% P2R3 2 3.3 45 150 40.0% dP2R4 2 4.1 45 186 DMSO 40.0% 20 4.0 10.0%P2R4 2 4.3 45 195 40.0% dP2R4 2 4.1 45 186 DMSO 40.0% 21 4.0 10.0%P0.4R8 0.4 7.7 9 70 40.0% dP2R5 2 5.3 45 241 DMSO 40.0% 22 4.0 10.0%P2R2 2 2.2 45 101 40.0% dP2R5 2 5.3 45 241 DMSO 40.0% 23 4.0 10.0% P2R32 3.3 45 150 40.0% dP2R5 2 5.3 45 241 DMSO 40.0% 24 4.0 10.0% P2R4 2 4.345 195 40.0% dP2R5 2 5.3 45 241 DMSO 40.0% 26 4.0  9.0% P0.4R8 0.4 7.7 970 36.0% dP0.4R10 0.35 9.8 8 78 DMSO 45.0% 27 4.0  9.0% P2R2 2 2.2 45101 36.0% dP0.4R10 0.35 9.8 8 78 DMSO 45.0% 28 4.0  9.0% P2R3 2 3.3 45150 36.0% dP0.4R10 0.35 9.8 8 78 DMSO 45.0% 29 4.0  9.0% P0.4R8 0.4 7.79 70 36.0% dP1R4 1 4.2 23 95 DMSO 45.0% 30 4.0  9.0% P2R2 2 2.2 45 10136.0% dP1R4 1 4.2 23 95 DMSO 45.0% 31 4.0  9.0% P2R2 2 2.2 45 101 36.0%dP2R3 2 2.7 45 120 DMSO 45.0% 32 4.0  8.0% P0.4R8 0.4 7.7 9 70 32.0%dP0.4R10 0.35 9.8 8 78 DMSO 50.0% 33 4.0  8.0% P2R2 2 2.2 45 101 32.0%dP0.4R10 0.35 9.8 8 78 DMSO 50.0% 34 4.0  8.0% P2R3 2 3.3 45 150 32.0%dP0.4R10 0.35 9.8 8 78 DMSO 50.0% 35 4.0  8.0% P0.4R8 0.4 7.7 9 70 32.0%dP1R4 1 4.2 23 95 DMSO 50.0% 36 4.0  8.0% P2R2 2 2.2 45 101 32.0% dP1R41 4.2 23 95 DMSO 50.0% 37 4.0  8.0% P2R2 2 2.2 45 101 32.0% dP2R3 2 2.745 120 DMSO 50.0% 38 4.0 10.0% P0.4R8 0.4 7.7 9 70 40.0% dP1R3 1 2.7 2361 DMSO 40.0% 39 4.0 10.0% P2R2 2 2.2 45 101 40.0% dP1R3 1 2.7 23 61DMSO 40.0% 40 4.0 10.0% P2R3 2 3.3 45 150 40.0% dP1R3 1 2.7 23 61 DMSO40.0% 41 4.0 10.0% P2R4 2 4.3 45 195 40.0% dP1R3 1 2.7 23 61 DMSO 40.0%42 4.0  9.0% P0.4R8 0.4 7.7 9 70 36.0% dP1R3 1 2.7 23 61 DMSO 45.0% 434.0  9.0% P2R2 2 2.2 45 101 36.0% dP1R3 1 2.7 23 61 DMSO 45.0% 44 4.0 9.0% P2R3 2 3.3 45 150 36.0% dP1R3 1 2.7 23 61 DMSO 45.0% 45 4.0  9.0%P2R4 2 4.3 45 195 36.0% dP1R3 1 2.7 23 61 DMSO 45.0% 46 4.0  8.0% P0.4R80.4 7.7 9 70 32.0% dP1R3 1 2.7 23 61 DMSO 50.0% 47 4.0  8.0% P2R2 2 2.245 101 32.0% dP1R3 1 2.7 23 61 DMSO 50.0% 48 4.0  8.0% P2R3 2 3.3 45 15032.0% dP1R3 1 2.7 23 61 DMSO 50.0% 49 4.0  8.0% P2R4 2 4.3 45 195 32.0%dP1R3 1 2.7 23 61 DMSO 50.0% 51 4.0 10.0% P2R2 2 2.2 45 101 40.0%dP0.4R8 0.35 7.9 8 63 DMSO 40.0% 52 4.0 10.0% P2R2 2 2.2 45 101 40.0%dP0.4R5 0.35 4.9 8 39 DMSO 40.0% 53 4.0 10.0% P2R2 2 2.2 45 101 40.0%dP1R2 1 2.1 23 48 DMSO 40.0% 54 4.0 10.0% P2R2 2 2.2 45 101 40.0%dP2R0.8 2 0.8 45 34 DMSO 40.0% 55 4.0 10.0% P2R2 2 2.2 45 101 40.0%dP2R2 2 1.5 45 68 DMSO 40.0% 56 4.0 10.0% P0.4R8 0.4 7.7 9 70 40.0%dP0.4R8 0.35 7.9 8 63 DMSO 40.0% 57 4.0 10.0% P0.4R8 0.4 7.7 9 70 40.0%dP0.4R5 0.35 4.9 8 39 DMSO 40.0% 58 4.0 10.0% P0.4R8 0.4 7.7 9 70 40.0%dP1R2 1 2.1 23 48 DMSO 40.0% 59 4.0 10.0% P0.4R8 0.4 7.7 9 70 40.0%dP2R0.8 2 0.8 45 34 DMSO 40.0% 60 4.0 10.0% P0.4R8 0.4 7.7 9 70 40.0%dP2R2 2 1.5 45 68 DMSO 40.0% 61 4.0 10.0% P0.4R8 0.4 7.7 9 70 40.0%dP0.4R10 0.35 9.8 8 78 DEGMEE 40.0% 62 4.0 10.0% P2R4 2 4.3 45 195 40.0%dP0.4R10 0.35 9.8 8 78 DEGMEE 40.0% 63 4.0 10.0% P0.4R8 0.4 7.7 9 7040.0% dP1R3 1 2.7 23 61 DEGMEE 40.0% 64 4.0 10.0% P2R4 2 4.3 45 19540.0% dP1R3 1 2.7 23 61 DEGMEE 40.0% 65 4.0 10.0% P0.4R8 0.4 7.7 9 7040.0% dP2R4 2 4.1 45 186 DEGMEE 40.0% 66 4.0 10.0% P2R4 2 4.3 45 19540.0% dP2R4 2 4.1 45 186 DEGMEE 40.0% 67 4.0 10.0% P0.4R8 0.4 7.7 9 7040.0% dP0.4R10 0.35 9.8 8 78 Diglyme 40.0% 68 4.0 10.0% P2R4 2 4.3 45195 40.0% dP0.4R10 0.35 9.8 8 78 Diglyme 40.0% 69 4.0 10.0% P0.4R8 0.47.7 9 70 40.0% dP1R3 1 2.7 23 61 Diglyme 40.0% 70 4.0 10.0% P2R4 2 4.345 195 40.0% dP1R3 1 2.7 23 61 Diglyme 40.0% 71 4.0 10.0% P0.4R8 0.4 7.79 70 40.0% dP2R4 2 4.1 45 186 Diglyme 40.0% 72 4.0 10.0% P2R4 2 4.3 45195 40.0% dP2R4 2 4.1 45 186 Diglyme 40.0% 73 4.0  9.0% P0.4R8 0.4 7.7 970 36.0% dP1R2 1 2.1 23 48 DMSO 45.0% 74 4.0  8.0% P0.4R8 0.4 7.7 9 7032.0% dP1R2 1 2.1 23 48 DMSO 50.0% 75 3.0 10.0% P0.4R8 0.4 7.7 9 7030.0% dP1R2 1 2.1 23 48 DMSO 50.0% 76 6.0  5.7% P0.4R8 0.4 7.7 9 7034.3% dP1R2 1 2.1 23 48 DMSO 50.0% 77 4.0  8.0% P0.4R5 0.4 4.7 9 4332.0% dP1R2 1 2.1 23 48 DMSO 50.0% 78 4.0  8.0% P1R2 1 2.1 23 48 32.0%dP1R2 1 2.1 23 48 DMSO 50.0% 79 4.0  8.0% P1R3 1 2.8 23 64 32.0% dP1R2 12.1 23 48 DMSO 50.0% 80 4.0  8.0% P0.4R5 0.4 4.7 9 43 32.0% dP1R3 1 2.723 61 DMSO 50.0% 81 4.0  8.0% P1R2 1 2.1 23 48 32.0% dP1R3 1 2.7 23 61DMSO 50.0% 82 4.0  8.0% P1R3 1 2.8 23 64 32.0% dP1R3 1 2.7 23 61 DMSO50.0% 83 4.0  8.0% P0.4R5 0.4 4.7 9 43 32.0% P0.4R5 0.35 4.9 8 39 DMSO50.0% 84 4.0  8.0% P1R2 1 2.1 23 48 32.0% P0.4R5 0.35 4.9 8 39 DMSO50.0% 85 4.0  8.0% P1R3 1 2.8 23 64 32.0% P0.4R5 0.35 4.9 8 39 DMSO50.0% 86 4.0 10.0% P2R4 2 4.3 45 195 40.0% dP2R4 2 4.1 45 186 DEGMEE40.0% 87 4.0  8.0% P0.4R5 0.4 4.7 9 43 32.0% dP1R2 1 2.1 23 48 DEGMEE50.0% 88 4.0  8.0% P1R2 1 2.1 23 48 32.0% dP1R2 1 2.1 23 48 DEGMEE 50.0%89 4.0  8.0% P1R3 1 2.8 23 64 32.0% dP1R2 1 2.1 23 48 DEGMEE 50.0% 904.0 10.0% P2R4 2 4.3 45 195 40.0% dP2R4 2 4.1 45 186 Diglyme 40.0% 914.0  8.0% P0.4R5 0.4 4.7 9 43 32.0% dP1R2 1 2.1 23 48 Diglyme 50.0% 924.0  8.0% P1R2 1 2.1 23 48 32.0% dP1R2 1 2.1 23 48 Diglyme 50.0% 93 4.0 8.0% P1R3 1 2.8 23 64 32.0% dP1R2 1 2.1 23 48 Diglyme 50.0% 95 4.010.0% P2R4 2 4.3 45 195 40.0% dP2R4 2 4.1 45 186 DMSO 40.0% 96 4.0  8.0%P0.4R5 0.4 4.7 9 43 32.0% dP1R2 1 2.1 23 48 DMSO 50.0% 97 4.0  8.0% P1R21 2.1 23 48 32.0% dP1R2 1 2.1 23 48 DMSO 50.0% 98 4.0  8.0% P1R3 1 2.823 64 32.0% dP1R2 1 2.1 23 48 DMSO 50.0%

The results of these formulations are illustrated in FIGS. 30 and 31.

Example 6—Risperidone's Formulations Preparation

The formulations described herein were based on organic solution ofpolymers prepared as in Example 1, containing as the drug, speridone.Typically, 0.4 grams of polymers, corresponding to a mix of a diblockcopolymer and a triblock copolymer in defined mass ratio, were dissolvedin 0.5 grams of dimethyl sulfoxide at room temperature overnight underconstant magnetic stirring. The next day, 100 mg of risperdone was addedto the polymer solution and stirred. The formulations were loaded in asyringe before use.

Three different formulations were selected for in vivo experiments. Thecomposition of these formulations is shown in Table C below. Theformulations were injected subcutaneously in the interscapular space ofmale rats (300 gr) at final dose of 21 mg/kg of risperidone. Bloodsamples were withdraw periodically and analyzed for risperidone and 9-OHrisperidone concentrations by LCMS/MS.

The formulations are shown in Table 4 below.

TABLE 4 Ra- Triblock copolymer (TB) Diblock copolymer (DB) tio RispRatio Ratio Solvent Exp DB/ % % PEG (LA/ DP- DP- % PEG (LA/ DP- DP- % noTB (w/w) (w/w) Code (kDa) EO) PEG PLA (w/w) Code (kDa) EO) PEG PLA Name(w/w) 5 1.5  2.5% 16.0% P2R3 2 3.5 45 158.6 24.0% dP2R3 2 2.7 45 122.7DMSO 57.5% 6 1.5  2.5% 16.0% P2R2 2 2.3 45 104.5 24.0% dP1R3 1 2.7 2361.4 DMSO 57.5% 10 1.5  5.0% 16.0% P2R2 2 2.3 45 104.5 24.0% dP2R3 2 2.745 122.7 DMSO 55.0% 11 1.5  5.0% 16.0% P2R3 2 3.5 45 158.6 24.0% dP2R3 22.7 45 122.7 DMSO 55.0% 12 1.5  5.0% 16.0% P2R2 2 2.3 45 104.5 24.0%dP1R3 1 2.7 23 61.4 DMSO 55.0% 16 0.7  5.0% 24.0% P2R3 2 3.5 45 158.616.0% dP0.4R5 0.35 4.9 8 39.0 DMSO 55.0% 17 1.5  5.0% 16.0% P3R2 3 2.368 156.8 24.0% dP2R3 2 2.9 45 131.8 DMSO 55.0% 19 1.5  5.0% 16.0% P3R3 33.2 68 218.2 24.0% dP2R3 2 2.7 45 122.7 DMSO 55.0% 20 1.5  5.0% 16.0%P1R4 1 3.8 23 86.4 24.0% dP2R3 2 2.9 45 131.8 DMSO 55.0% 21 0.7  5.0%24.0% P1R4 1 3.8 23 86.4 16.0% dP0.4R5 0.35 4.9 8 39.0 DMSO 55.0% 22 1.510.0% 16.0% P2R2 2 2.3 45 104.5 24.0% dP2R3 2 2.7 45 122.7 DMSO 50.0% 231.5 10.0% 16.0% P2R3 2 3.5 45 158.6 24.0% dP2R3 2 2.7 45 122.7 DMSO50.0% 25 0.7 10.0% 24.0% P2R3 2 3.5 45 158.6 16.0% dP0.4R5 0.35 4.9 839.0 DMSO 50.0% 26 1.5 10.0% 16.0% P3R3 3 3.2 68 218.2 24.0% dP2R3 2 2.745 122.7 DMSO 50.0% 27 1.5 10.0% 16.0% P1R4 1 3.8 23 86.4 24.0% dP2R3 22.9 45 131.8 DMSO 50.0% 28 0.7  5.0% 18.0% P1R4 1 3.8 23 86.4 12.0%dP0.4R5 0.35 4.9 8 39.0 DMSO 65.0% 29 0.7 10.0% 24.0% P1R4 1 3.8 23 86.416.0% dP0.4R5 0.35 4.9 8 39.0 DMSO 60.0% 30 0.7 10.0% 18.0% P1R4 1 3.823 86.4 12.0% dP0.4R5 0.35 4.9 8 39.0 DMSO 60.0% 31 0.7 10.0% 18.0% P2R32 3.5 45 158.6 12.0% dP0.4R5 0.35 4.9 8 39.0 DMSO 60.0% 32 1.5 10.0%12.0% P1R4 1 3.8 23 86.4 18.0% dP2R3 2 2.9 45 131.8 DMSO 60.0% 33 1.510.0% 12.0% P3R3 3 3.2 68 218.2 18.0% dP2R3 2 2.7 45 122.7 DMSO 60.0% 340.7 15.0% 18.0% P1R4 1 3.8 23 86.4 12.0% dP0.4R5 0.35 4.9 8 39.0 DMSO55.0% 35 1.5 15.0% 12.0% P2R2 2 2.3 45 104.5 18.0% dP2R3 2 2.7 45 122.7DMSO 55.0% 36 0.7 15.0% 18.0% P2R3 2 3.5 45 158.6 12.0% dP0.4R5 0.35 4.98 39.0 DMSO 55.0% 40 0.7 10.0% 24.0% P1R4 1 3.8 23 86.4 16.0% dP0.4R50.35 5.02 8 39.9 DMSO 60.0% 41 0.7 10.0% 18.0% P2R3 2 3.5 45 158.6 12.0%dP0.4R5 0.35 5.02 8 39.9 DMSO 60.0% 42 0.7 10.0% 24.0% P1R4 1 4.0 2389.8 16.0% dP0.4R5 0.35 5.02 8 39.9 DMSO 60.0% 43 0.7 10.0% 24.0% P1R4 13.8 23 86.4 16.0% dP0.4R5 0.35 5.02 8 39.9 DMSO 60.0% 44 0.7 10.0% 24.0%P1R4 1 4.0 23 89.8 16.0% dP0.4R5 0.35 5.02 8 39.9 DMSO 60.0%

The results of these formulations are illustrated in FIGS. 32 and 33.

Example 7—Ivermectin's Formulations Preparation

The formulations described herein were based on organic solution ofpolymers prepared as in Example 1, containing as the drug, ivermectin.Typically, 0.4 grams of polymers, corresponding to a mix of a diblockcopolymer and a triblock copolymer in defined mass ratio, were dissolvedin 0.55 grams of dimethyl sulfoxide at room temperature overnight underconstant magnetic stirring. The next day, 50 mg of ivermectin was addedto the polymer solution and stirred until complete dissolution. Threedifferent formulations were selected for in vivo experiments. Thecomposition of these formulations is shown in Table 5 below. Theformulations were injected subcutaneously in the interscapular space ofmale dogs (10 to 17 kg) at a final dose of 0.6 mg/kg of ivermectin.Blood samples were withdraw periodically and analyzed for ivermectinconcentrations by LC/MS/MS.

The formulations are shown in Table 5.

TABLE 5 Triblock copolymer (TB) Diblock copolymer (DB) IVM Ratio RatioSolvent Exp Ratio % % PEG (LA/ DP- DP- % PEG (LA/ DP- DP- % no DB/TB(w/w) (w/w) Code (kDa) EO) PEG PLA (w/w) Code (kDa) EO) PEG PLA Name(w/w)  9 1.7 5.0% 15.0% P3R3 3 3.2 68 218 25.0% dP0.4R5 0.35 4.9 8 39DMSO 55.0% 10 1.7 5.0% 15.0% P2R3 2 3.5 45 159 25.0% dP2R3 2 2.9 45 132DMSO 55.0% 11 1.7 5.0% 15.0% P2R5 2 5.3 45 241 25.0% dP2R2 2 2.3 45 105DMSO 55.0%

The results are illustrated in FIG. 34.

Example 8—Injectability of Differing Compositions

Various formulations were tested for injectability using formulationswith different ratios of triblock (TB) and diblock (DB). Differentsolutions in DMSO based on a mixture of the triblock copolymer P6R1(TB)and the diblock copolymer dP2R4(DB) were prepared.

A 50% weight %/weight % polymer/formulation mass was used in theseviscosity experiments. The weight %/weight % of triblock to diblock thatwas used in this experiment were the following: 50 wt. %:0 wt. %, 45 wt.%:5 wt. %, 20 wt. %:5 wt. %, 35 wt. %:15 wt. %, 15 wt. %:10 wt. %, 25wt. %:25 wt. %, 10 wt. %:15 wt. %, 15 wt. %:35 wt. %, 5 wt. %:20 wt. %,5 wt. %:45 wt. % and 0 wt. %:50 wt. %.

The injectability results are shown in FIG. 3.

Example 9—In Vitro Release Assay

100 to 500 mg of formulation was added to 20 to 50 ml of physiologicalbuffer. The physiological buffer that was used was KRT containing 50 mlKrebs/Ringer/Tris (KRT) buffer pH 7.4, which is 143 mM Sodium Chloride,5.1 mM Potassium Chloride, 2.7 mM Calcium Chloride, 1.34 mM MagnesiumSulfate, 25 mM Tris-CI pH 7.4 and 0.1% sodium azide. Upon injection, thesolvent diffused away from the formulation and the remaining polymerformed a solid biodegradable implant within the aqueous environment.

In order to maintain sink conditions, for drug release, the releasemedium was maintained under constant shaking at 180 rpm (Unimax 1010apparatus, Heidolph) at 37° C. At pre-determined time intervals, mediaare collected and analyzed by HPLC. The amount of the GLP-1 analoguepeptide M53, released from the formulation was calculated from acalibration curve. The concentration of M53 ranged between 0 and 5 mg/mlor it ranged between 0 and 200 μg/ml.

The results are shown in FIG. 4 and FIG. 5. FIG. 5 illustrates therelease rate of formulations 177, 224, 225, 246 and 250 as shown inTable 1, while FIG. 4 shows the cumulative release of drug from theindicated formulations.

When the GPL-1 analogue was incorporated into the polymer solution, itwas encapsulated within the polymer matrix as it solidified. The drugwas then released either by diffusion inside the matrix or bybiodegradation of the matrix.

Example 10—Pharmacokinetic Study

Several formulations were tested in a pharmacokinetic study in rats.Compositions containing 1 mg of drug per animal of the formulations of177, 224, 225, 246 and 250, as set forth in Table 1 were subcutaneouslyadministered to rats. Blood samples were collected into EDTA tubes atdifferent time points, centrifuged and the plasma from each time pointwas retained. The plasma samples were analyzed by LC/MS/MS andquantified for drug content. Results are presented as ng/ml of plasmameasured over time.

The results of one pharmacokinetic study are shown in FIG. 6. As shownin this Figure three of the five formulations sustain plasmaconcentration higher than 0.1 ng/ml for more than 28 days while giving amoderate initial drug burst release below ng/ml.

Example 11—Blood Glucose Levels

Blood glucose levels with patients suffering from diabetes type 2 aretaken prior to treatment. A control group having no treatment is usedfor this study. Patients of either gender are used in this studyprovided that they have diabetes type 2 and are between the ages of 35and 60.

A GPL-1 analogue is formulated according to Examples 1 and 2 and has thechemical characteristics of number 230 in Table 1. The injectable liquidthat is obtained is then injected into several patients at a dosage of 8mg/ml. The control group is given PBS.

The amount of blood sugar levels and fructosamine is then measured for aperiod of 30 days, twice weekly, before meals and 2 hours after meals.The amounts of blood glucose after treatment are measured and theresults are averaged. The values are shown in Table 6:

TABLE 6 Blood Glucose Blood Glucose Level Before Level After Fruc- WeekPatient Meals Meals tosamine number number in mmol/l In mmol/l μmolPrior to 1 150 190 300 Treatment 2 130 175 320 3 200 230 330 4 220 240360 1 1 90 150 280 2 98 110 290 3 120 160 330 4 215 240 365 2 1 92 120275 2 95 100 287 3 118 158 300 4 210 230 370 3 1 92 110 270 2 98 101 2753 115 155 280 4 211 222 385 4 1 93 110 260 2 85 100 260 3 110 150 265 4223 244 365

Normal results for the glucose levels before meals range from 80 to 120mmol/l. Normal results for the glucose levels after meals should be 160mmol/l or less. Normal fructosamine levels are under 265. Between 265and 280 indicates excellent blood glucose control; 280 and 500 indicatesgood blood glucose control; between 320 and 340 indicates fair bloodglucose control; and over 350 indicates poor blood glucose control.

Patient 4 was administered the placebo.

These results show that when administered the biodegradable drugdelivery compositions of the present invention are effective to treatdiabetes type 2.

While the invention has been described in terms of various preferredembodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions and changes may be made withoutdeparting from the scope thereof. Accordingly, it is intended that thescope of the present invention be limited by the scope of the claims,including equivalents thereof.

What is claimed is:
 1. A biodegradable drug delivery compositioncomprising: (a) a biodegradable triblock copolymer present in an amountof 3.0% to 45% (w %/w %) of the total composition having the formula:Poly(lactic acid)v-poly(ethylene glycol)w-poly(lactic acid)x wherein vand x are the number of repeat units ranging from 24 to 682 and w is thenumber of repeat units ranging from 4 to 273 and v=x or v≠x; (b) abiodegradable diblock copolymer present in an amount of 8.0% to 50% (w%/w %) of the total composition having the formula:methoxy poly(ethylene glycol)y-poly(lactic acid)z wherein y and z arethe number of repeat units y ranging from 3 to 45 and z ranging from 7to 327, wherein the ratio of the biodegradable triblock copolymer of (a)and the biodegradable di block copolymer of (b) is 1:3 to 1:8 or 1:1 to1:19 or 3:2 to 1:19 in said biodegradable drug composition which isinsoluble in water; and (c) an organic solvent present in an amount of40%-74% (w %/w %) of the total composition; and (d) at least onepharmaceutically active principle.